Everyone knows that sleep is important. Yet, as a nation, we’re sleeping a full hour less per night on average than we were just ten years ago.(Jean-Louis, Kripke et al. 2000) This trend is certainly not new; for more than 25 years, Americans have been sleeping less and less each night and, in a recent study, up to half of all American adults report having sleep problems in any one year. (Becker 2006) Of all the sleep disorders, insomnia is, by far, the most common, affecting nearly 70 million of us; in a recent sur- vey, 35% of respondents had insomnia every night and nearly 60% reported insomnia at least a few nights per week. Sleep problems have been dubbed “a hallmark of modern living.”(Bollinger, Bollinger et al. 2010)

Why this is happening is not clear. Is it because we often favor work, play, socializing, or learning over sleep? Are we sleeping less because of problems with our local living environ- ment? Are sleep disturbances really a sign of some underlying disease? Is the problem, as many want to suggest, simply stress? While most people do experience some level of stress in their lives, one theory is that it’s a deficiency in positive coping skills, rather than the stress itself, that lets the body veer out of balance and causes sleep problems. Also interesting to note, recent re- search suggests that high positive emotions (not just high nega- tive emotions) can also cause a poor night’s sleep, too.(Baglioni, Spiegelhalder et al. 2010)

Given that so many of us aren’t getting enough high-quality sleep, it is worthwhile to educate ourselves on how sleep or sleep deprivation affects our health. What do scientists know about sleep? Why do we even need to sleep? How many hours of sleep do we really need each night and what happens if we sleep for less than this optimal number? Equipped with answers to these questions, we will be more apt to make healthy choices regarding sleep.

WHAT IS KNOWN ABOUT SLEEP?

What Happens During Sleep & Why Do We Need It?

Sleep may have given humans an evolutionary advantage, pro- ducing immobility at times when activity would be unproductive (preventing wasteful energy expenditure) or dangerous (prevent- ing unnecessary exposure to predators).

Sleep was first described physiologically in the 1930s(Loomis, Harvey et al. 1935) and our understanding was greatly enhanced by the discovery of rapid eye movement (REM) in the 1950s.(Aserinksy and Kleitman 1953) Our sleep is usually divided into various phases, based on the differences in brain activity throughout the night. During these various phases, our bodies repair and our memories are organized.

Current research suggests that the interplay between ho- meostasis and circadian rhythm determines our sleep pattern. Homeostasis, which is the ability of the body to adjust its physi- ology in response to fluctuations in the outside environment and the weather, would have us sleeping in small increments through- out the day to balance our wakeful hours.

Circadian rhythm, on the other hand, is the 24-hour cycle in physiological functioning found in most living organisms. Until recently, it was assumed that the human circadian rhythm was also 24 hours in length. However, there are several curious anomalies to human circadian rhythm for which a clear answer is not yet available. Two unique features of the human circadian system are (1) an internal tendency toward “desynchronization,” in which core body temperature has a cycle of about 25 hours, and (2) a sleep-waking cycle of about 30 hours.(Yamanaka, Honma et al. 2009) While it is now known that exposure to bright light appears to re-synchronize the body to the planetary 24-hour cycle,(Yamanaka, Honma et al. 2009) it is not yet clear why the body’s day/night clock is longer than the duration of one day.

A comparison to simpler organisms is also curious: hu- man beings experience drastic disturbances to our biological clocks with sudden shifts in our daily schedules, leading to sleep disorders, mood disorders, and impaired performance. Honey- bees, on the other hand, do not have this liability and are able to very quickly adjust their own physiological rhythms when they are subjected to drastic changes in their work schedules. It is the complex and highly interactive social environment of the honeybees that help them in making these nimble adjustments. (Shemesh, Eban-Rothschild et al. 2010) Perhaps this tendency for the human nervous system to drift toward desynchronization is the result of having a very well-developed brain; it is analogous to high-performance sports cars, where greater sophistication requires more frequent maintenance and tune-ups.

The Problem Doesn’t Start at Bedtime

One reason a person’s night can become disturbed is because their day is out of balance. If you can’t get to sleep, the problem didn’t begin just at that moment, but can have its roots much further back in time. In the physiology of the body, timing is a critical issue and a person’s misuse of time can lead to loss of coordina- tion between important body functions, a term called chrono- disruption. Whether this chrono-disruption, or “physiological bad timing,” is the result of poor sleep, or can itself cause sleep disorders, is not clear. However, both common sense and the following research data would suggest that conducting oneself contrary to one of nature’s most fundamental cycles of time, the diurnal rhythm (or daytime-nighttime cycles), is probably not a good idea.

The Role of Light

Light plays a key role in our sleep cycle, centered on critical light-receptive cells on the retina of the eye that help regulate not only circadian timing and neuroendocrine function, but also a person’s behavioral responses. When exposed to bright light, those photoreceptive cells stimulate parts of the brain that are not image-forming centers, but serve primarily as the body’s master biological clock. Furthermore, when the retinas are exposed to light much more dim than sunlight (as is most indoor lighting),

this light deficiency causes an information deficiency in the brain that sets in motion a chain-reaction of harmful side-effects in- cluding insomnia, depression, and impaired cognition.(Turner, van Someren et al. 2010) In other words, if you spend most of your daytime hours indoors, you may well be “light deficient.” This daytime light deficiency may be a common cause of night- time sleep disorders.

Recent research from the Institute of Medical Microbiology and Hygiene in Germany provides detailed insights that were first explained by 3rd Century BC medical texts from China: That circadian rhythm is controlled by both central control systems in the brain as well as local/regional cellular centers in other body tissues. For the immune system specifically, the effect of sleep deprivation can be to inhibit immune function by disrupting the circadian rhythms within immune system cells themselves, which in turn may be a long-term consequence of disturbances in hormonal cycles and circadian rhythms. These researchers also suggest that sleep, through the lowering of body temperature, “primes” the cells of the immune system and by doing so provides a timing signal for circadian clocks in the blood cell-producing bone marrow. It is chronic sleep disruption that desynchronizes these different time clocks, which in turn leads to dysregulation of the body’s immune responses.(Bollinger, Bollinger et al. 2010)

Sleep & Learning

One important function of sleep that is of interest to students is that it consolidates or reorganizes memory.(Kopasz, Loessl et al. 2010) Based on the results of three separate meta-analyses of 17 studies conducted by a team in the netherlands, successful learning and school performance are linked to sleep quality, sleep duration, and the absence of daytime sleepiness.(Dewald, Meijer et al. 2010) This means that in order to remember what you stud- ied during the day, you need to get a good night’s sleep at night. Renowned sleep researcher Matthew P. Walker at the University of California at Berkeley has also added important understand- ing to the relationship between sleep and learning; not only does sleep help the brain integrate individual bits of information into broader themes and patterns, it may fundamentally enhance the brain’s capacity for creativity. (Walker, 2009)

NON-REM & REM: THE TWO STATES OF SLEEP

Non-REM Sleep

This is the “deep” phase of sleep, which conserves energy, restores the central nervous system (CnS) or components of the CnS (such as the frontal cortex and glycogen stores), cools the body and the brain, and promotes immune function.(Dement and vaughan 2000)

REM Sleep

This is the more active “rapid-eye-movement” (REM) phase of sleep that helps the mind with psychological and/or emotional adaptation. By virtue of its stimulating effect, REM sleep also promotes development of the central nervous system and compensates for the deep brain stillness and brain cooling that happens during non-REM sleep. Furthermore, REM sleep facilitates periodic awakening to help a person survey their environment.(Dement and vaughan 2000)

SLEEP AND THE IMMUNE SYSTEM

When we get sick, we tend to feel tired and sleep more. But is this coincidental or is sleep a recuperative immune function? One study showed that infected rabbits that slept more had a better prognosis, suggesting that sleep might enhance recovery. But it’s unclear whether other factors, such as stress, might have been the cause of disrupted sleep in the rabbits that didn’t fare so well. (Dement and vaughan 2000)

In humans, there’s an increasing amount of research evi- dence that suggest that the right amount of sleep might prolong life; one study of 185 people aged 60 to 80 found that the quality of their sleep predicted the length of their remaining lifespan. (Dew, Hoch et al. 2003)

As more research is conducted on this subject, it is hoped that the exact nature of the relationship between sleep and the immune system’s role in controlling tumor growth can be ascertained.

GETTING A “GOOD” NIGHT’S SLEEP

What is the Definition of Good Sleep?

What constitutes “good” sleep is highly subjective, but most people would agree that an evening of high quality sleep is one in which you’re able to fall asleep quickly, stay asleep throughout the night, and wake up feeling refreshed. To achieve this sort of sleep, there are several approaches, from behavioral to pharmacological.

Good sleep can be defined in terms of sleep architecture – it is characterized by an optimal length of each sleep stage (which is age and gender specific), an appropriate distribution of sleep stages throughout the night, and a low frequency of arousal from sleep. Good sleep can also be defined in terms of general physi- ological activity; non-REM sleep, which constitutes approxi- mately 80% of sleep in a night (when optimal), is characterized by reduced physiological activity, such as reduced metabolism.

A person’s subjective assessment of their sleep quality and daytime functionality also define their “sleep health.” These tend to correlate well with objective performance estimates of daytime functioning.(Dement and vaughan 2000)

WHAT ARE THE DIFFERENT TYPES OF SLEEP DISORDERS?

Sleep Debt

Homeostasis in the human body dictates that for every two hours of wakefulness, we require one hour of sleep. If sleep cycles become disturbed, we end up “owing” hours of sleep and these hours are our “sleep debt.” Sleep debt is cumulative and carries over from one day to the next. The number of hours of sleep required per day varies with age and with individuals. On average, adults need to sleep eight hours per day, but this decreases with age.(neikrug and Ancoli- Israel 2009) Children and teens require ten hours per day on average.

Chronic Versus Acute Sleep Loss

While chronic sleep loss has been shown to be harmful to well-being, there is growing evidence that the occasional acute sleep disturbance might actually boost the immune system. (Rechtschaffen, Gilliland et al. 1983; Everson 1993; Landis and Whitney 1997)

In a study involving sleep-deprived rats, the animals’ ability to defend against infection was dependent on the length of their sleep deprivation. Evolutionarily, it may be that the immune sys- tem needs to be enhanced by brief total sleep loss, such as when being hunted by a predator. But without sleep, the immune sys- tem does eventually fail.(Dement and vaughan 2000)

WHAT CAUSES OR EXACERBATES POOR SLEEP?

In addition to the obvious causes of poor sleep that are a function of lifestyle and choice, there are many medical problems that can lead to poor sleep, some of which we review here.

Serotonin Dysfunction

A core part of brain function involves the compound serotonin, which is a neurotransmitter that is biochemically derived from the amino acid tryptophan and is critical to the transmission of nerve signals between neurons. The cells which produce this neurotransmitter, although few in number, are essential to the regulation of important brain functions including those that fol- low circadian rhythms: Sleep and waking, thinking, mood, appe- tite, sexual interest, body temperature, and behavioral regulation of aggression and impulse.(Jacob and Fornal 1995) Insufficient production of serotonin has widespread effects on the brain, play- ing a role in insomnia and mood disorders including depression, anxiety, and obsessive compulsive and bipolar disorders.(Davis, Charney et al. 2002)

Chronic Pain & Sleep

While people generally recognize that chronic pain can interfere with sleep,(Wells, Li et al. 2009) new research has shown that the effect goes in both directions, and that sleep disturbance con- tributes to increased pain levels.(Moldofsky 2010)

In people with cancer, there frequently occurs a combination of pain, fatigue, and sleep disturbance. A recent meta-analysis has provided evidence that these symptoms can all be improved by guided imagery/hypnosis and cognitive-behavioral therapy and coping-skills training, relaxation training, meditation training, and music.(Kwekkeboom, Cherwin et al. 2010)

Obstructive Sleep Apnea

In the Wisconsin Sleep Cohort study, which began over 20 years ago and monitors the sleep health of over 3000 people, re- searchers discovered that for every 10 persons, 1 to 2 suffer from untreated sleep apnea.(Young, Palta et al. 2009) Sleep apnea is a breathing problem in which a sleeping person frequently snores, often becoming louder until interrupted by a period of silence in which breathing stops and is then restarted after a loud gasping. This snoring returns often very frequently during the night. The problem stems from anatomical abnormalities in the back of the throat; usually, the body can compensate by the brain’s input to the muscles which dilate the upper airway, but those signals are suppressed during sleep, leading to the collapse of the airway in the throat.(Dempsey, veasey et al. 2010)

It has long been known that the frequent nighttime episodes of lower oxygen levels that result from this airway collapse are linked to sexual problems (erectile dysfunction), cardiovascular problems (heart disease, high cholesterol, stroke, and swelling in the legs), performance deficits (daytime drowsiness, waking up groggy, depression, hyperactivity, insomnia, memory problems, headaches, personality changes, cognitive impairment, and poor concentration), liver disease (liver inflammation and fibrosis), and to an increasingly more common health problem: diabetes. (Zias, Bezwada et al. 2009; Brondel, Romer et al. 2010; Drager, Jun et al. 2010; Eastwood, Malhotra et al. 2010; Tian, Zhang et al. 2010; Tsai 2010)

The relationship of sleep problems to diabetes has been much better understood with recent research. Compared with men, the odds that a woman with sleep apnea developing diabetes are 11 to 1, based on the results of a 16-year follow-up study. (Celen, Hedner et al. 2010) Furthermore, the type of sleep prob- lems a person has can predict their subsequent risk of developing diabetes: sleep of short duration (less than 5 to 6 hours per night), sleep of very long duration (over 8 to 9 hours per night), or dif- ficulty in getting to sleep or maintaining sleep all increase the risk of developing diabetes between 28% and 84% (nearly double). (Cappuccio, D’Elia et al. 2010)

While sleep apnea can sometimes be successfully treated by surgery,(Ye, Liu et al. 2009) there are no clearly established evidence-based guidelines for assessing suitability for surgery as based on a patient’s degree of airway obstruction and the likeli- hood of receiving surgery depends on the level of clinician expe- rience and resources available at individual hospitals.(Georgalas, Garas et al. 2010)

Although not widely used by sleep medicine centers, it has been known for the past 15 years by Japanese researchers that abnormal positioning of the jaw during sleep (too far to the back) can cause sleep apnea.(Masumi, nishigawa et al. 1996; Smith 1996) Continued research on this discovery in Japan, China, Italy, and the US has led to the development of small splints that can be inserted into the jaw, helping move the jaw forward and opening up the airway at the back of the throat to allow for better air passage during sleep. Besides improving sleep, this also helps correct the heart rate abnormalities caused by sleep apnea.(Smith 1996; villa, Bernkopf et al. 2002; Coru- zzi, Gualerzi et al. 2006; Arai, nakayama et al. 2007; Tsuda, Tsuda et al. 2007; Zeng and Gao 2009) Dentists who have special training can use an x-ray examination of the skull and jaw to identify whether or not a patient is likely to benefit from a splint(Monteith 2004) and can also provide special exercises that a patient can perform to improve jaw positioning.(Ueda, Almeida et al. 2009)

In people not helped by the splint or exercises, sleep apnea can still be successfully treated by a device called C-PAP, which blows air at a prescribed pressure through a mask worn during sleep, helping keep the airway open. Although awkward and unsexy, the devices can still be effective. A new oral device based on the splint, called OPAP, was tested at Stanford University for use in combination with C-PAP and recently received FDA approval (more information available at opaphealthcare.com).

Although overnight evaluation and treatment at clinical sleep centers can be helpful in treating obstructive sleep apnea, it is nevertheless a daunting (and expensive) process. Encour- agingly, researchers at the University of Saskatchewan this year published an excellent clinical study demonstrating that at-home diagnosis and treatment using a take-home device was just as good as that same procedure being done at a sleep center. This equivalence was demonstrated in terms of outcomes in sleepiness scores, sleep quality, quality of life, blood pressure, and compliance in the use of the CPAP device.(Skomro, Gjevre et al. 2010)

Hepatitis C

A wide range of other physical ailments can also cause sleep prob- lems. In hepatitis C, up to 60% of patients will experience newly diagnosed sleep problems, which is encouragingly reduced to 30% of patients who undergo treatment with interferon.(Socka- lingam, Abbey et al. 2010)

Cancer

It is known that anxiety and sleep problems can follow a cancer diagnosis.(Price, Zachariae et al. 2009; Savard, villa et al. 2009) It can also work in the other direction: sleep problems (and the resulting disturbances in day/night variations of melatonin levels in the blood) can predate diagnoses of breast and prostate cancer by many years. new research from Case Western Reserve University has found that sleeping less than 6 hours per night increases the risk of colon cancer by nearly 50%.(Thompson, Larkin et al. 2010) Additionally, in a large- scale survey of 363 people newly diagnosed with breast cancer, researchers found that compared to age-matched controls, those diagnosed were 40% more likely to have reported keep- ing lights on while sleeping, 40% more likely to sleep during the daytime, and 20% more likely to regularly close the win- dow shades while sleeping at night. These results, while not statistically significant, nevertheless suggest a plausible theory. (Li, Zheng et al. 2010)

Hospitals

As the intention in going to a hospital is usually to get better, it is ironic that the noise levels in most hospitals can interfere with pa- tients’ sleep, particularly in intensive care units.(xie, Kang et al. 2009) This is especially problematic in that poor sleep is associ- ated with poor intensive care unit medical outcomes.(Weinhouse, Schwab et al. 2009; Weinhouse and Watson 2009)

WHAT ARE THE CONSEQUENCES OF NOT SLEEPING WELL?

Your Own Safety and the Safety of Others

A curious anomaly in human performance is that people often overestimate their own abilities to perform critical tasks, such as driving. Most people also misjudge their level of sleepiness and amount of sleep debt and are usually wrong about how likely they will fall asleep in the near future, which leads people to think they’re alert enough to drive when they really aren’t. Unfortunately, sleepiness behind the wheel is a major cause of fatal crashes(Abe, Komada et al. 2010; Sagaspe, Taillard et al. 2010; valent, Di Bartolomeo et al. 2010; vennelle, Engleman et al. 2010) and people with sleep apnea are six times more likely to have traffic accidents than those people without this problem. (volna and Sonka 2006) And when you add alcohol to the mix, combining even a small amount of alcohol while you’re already tired is the functional equivalent of having a lot of alcohol when you’re well-rested.(Rodenstein 2009)

Medical Errors

Researchers at the Institute of Medicine, an independent federal research agency, recently published a comprehensive report in which they found that the frequency of serious medical errors goes up when medical residents are deprived of sleep. Medical residents are physicians who have graduated from medical schools, but are practicing medicine in a hospital or clinic under the supervision of fully licensed physicians. Almost all hospital stays involve being cared for by a medical resident at some point.

The problem involving medical errors centers around the difference between being awake and being competently alert. It is possible to use stress (adrenaline), exercise, and caffeine or other stimulant drugs to stay awake. It is not possible, however, to use these stimulants to overcome the damaging impact of sleep depri- vation on job performance and judgment.(Czeisler 2009) In this way, medical personnel being underslept leads directly to medical errors because of impaired skill and judgement.

This poses numerous ethical dilemmas for hospitals. Should hospitals limit physicians’ work hours to protect patient safety? Because sleep disorders increase substantially with age, should medical personnel be tested for suitability for long work shifts over the course of their careers?(Czeisler 2009)

Resident physicians at US hospitals are allowed to work for up to 30 hours in one shift. (Olson, Drage et al. 2009) Two-thirds of medical residents report that “sleep loss and fatigue have a major impact on my personal life” and nearly half report that “sleep loss and fatigue have a major impact on my work.”(Rosen, Gimotty et al. 2006) The number of medi- cal errors that can result from these working conditions are, not surprisingly, quite high. For example, in a survey of 254 internal medicine resident physicians, 41% reported that their own fatigue directly caused the most serious medical error they had made, and that a third of these errors led to the death of a patient.(Wu, Folkman et al. 1991)

Lurking beneath these issues of human performance are the financial incentives for hospitals, which depend on the profit mar- gin between payments they receive from Medicare or third party insurers and the low wages they pay to their resident physicians- in-training.

Emotional & Psychiatric Health

Mood disorders, anxiety, dementia, emotional instability, and the use of antidepressant medications, are all associated with sleep disorders. In many of these disorders, it is not yet known which came first: the sleep problem or the psychiatric problem.(Diekel- mann, Wilhelm et al. 2009; Sateia 2009; Teman, Tippmann- Peikert et al. 2009)

Lack of Sleep May Lead to Overeating

In a study published March 2010 in the American Journal of Clinical nutrition, researchers reported, “sleep restriction could be one of the environmental factors that contribute to the obe- sity epidemic.” They closely followed the eating, sleeping, exer- cise, and eating activities of 12 healthy young men during two 48-hour periods. The researchers first observed those men for a two-day “baseline” or control period. They then followed them closely for an active two-day study period. On the first day, the men in the study were asked to go to bed at 12 am and wake up at 8 am; on the second day, they went to bed at 2 am and woke up at 6 am. What the researchers found was that after sleeping only four hours, the men in the study ate an average of 22% (or over 500) more calories per day than they did after eight hours of sleep.

HOW TO SLEEP BETTER: UNDERSTANDING OUR NEEDS AND PATTERNS

The first step to better sleep is to determine your sleep needs and circadian pattern. This can be accomplished by keeping notes on the times when you are at peak alertness during the day. These peaks in alertness are ideal times for tackling your most challeng- ing tasks. During troughs in alertness are appropriate times for napping, resting, not driving, and other inconsequential tasks. Having then determined those optimal cycles, you can then make choices that help you lead a lifestyle that respects your body’s natural sleep patterns.

Treat sleep like exercise and diet. It is essential to pay atten- tion to it and manage it for the sake of health and longevity.

Sleep Clinics

A website sponsored by the American Academy of Sleep Medi- cine provides a list of sleep clinics. This site can be searched geo- graphically and is available at www.sleepcenters.org.

Music

A recent study from researchers in Taiwan found that people who listened to soft, slow music at bed time “experienced physical changes that aided restful sleep, such as lower heart and respira- tory rates.” Participants listened to 45-minute relaxing music tapes at bedtime for three weeks. The study found that this resulted in “significantly better sleep quality” and that “sleep improved weekly, indicating a cumulative dose effect.” (Lai and Good 2005)

Yoga

A recent study showed that participants who attended regular yoga sessions reported “significantly lower sleep disturbance” as com- pared to a control group. In this study, the benefits of yoga included better quality of sleep, the ability to fall asleep quicker, longer sleep duration, and less use of sleep medications. (Cohen 2004)

WHAT ABOUT WORKING NIGHT SHIFTS?

European researchers have done extensive research on the effect of shift-work (defined as work at times other than the normal 9 to 5 work schedule) and found that the people whose sleep is impacted most by their work hours are those who work nights and early-mornings as well as those who work slowly backward- rotating shifts (as compared to rapidly forward-rotating shifts). (Sallinen and Kecklund 2010)

PHARMACOLOGICAL APPROACHES

Melatonin

Melatonin was first isolated roughly 50 years ago(Lerner, Case et al. 1960) and is a chemical that has been functionally linked to the body’s regulation of circadian(Malpaux, Migaud et al. 2001; Malpaux, Tricoire et al. 2002) and seasonal rhythms,(Reiter 1993) immune function,(Guerrero and Reiter 2002) and tumor inhibition.(Blask, Dauchy et al. 2002; Blask, Sauer et al. 2002) Melatonin is not a hypnotic or soporific but rather seems to func- tion as a chemical that “opens the gate” to sleep, not something that induces sleep itself.(Kennaway and Wright 2002)

Melatonin production takes place in the brain and is mostly regulated by ambient light; only during darkness does the major- ity of melatonin production take place. The amount of melatonin an individual produces is also genetically determined, but age can also be a factor as people tend to produce less melatonin as they grow older.

Melatonin: Timing Is Everything

Researchers have revealed a substantial body of evidence on how melatonin influences sleep. That some of this information is conflicting suggests that the full story is not yet fully understood. Medicine is a work in progress and new research in the next few years should help fill in some of the gaps in knowledge on this important topic.

Melatonin has been shown to “open the gates” to sleep, so timing is very important depending on the desired effect.

IN GENERAL
Bright light exposure after darkness should be avoided since it disrupts the melatonin rhythm and alters the circadian clock. When used for night-time sleep pro- motion, melatonin is best taken 30 minutes before desired sleep onset.

WHEN TAKEN AT DUSK
Melatonin advances the internal clock, making you feel like it’s later than it really is.

WHEN TAKEN EARLY AT DAWN
Melatonin delays the internal clock, making you feel like it’s earlier than it really is.

TAKIN MELATONIN WHEN TRAVELING EAST
If you were traveling from san Francisco to Paris, take melatonin at dusk san Francisco time (which may be on the plane). Then take melatonin at dusk Paris time when you’ve arrived. a day or so before head- ing home, take melatonin at dusk Paris time and then, once home, at dusk san Francisco time.

TAKING MELATONIN WHEN TRAVELING WEST
If you were traveling from san Francisco to Beijing, take melatonin once you arrive at dusk Beijing time. Before you leave, take melatonin at dusk Beijing time and then, once home, at dusk san Francisco time. note: it has been suggested that westbound travel causes less jetlag. also, it has been suggested that melatonin is not very effective for westbound travel of less than four time zones.

Source: Reiter 2003

Tryptophan

Dietary tryptophan, which can cross the blood-brain barrier,(Young and Gauthier 1981) is a precursor to serotonin production in the brain. The levels of serotonin in the brain can be increased by up to two-fold with a dose of tryptophan of 3,000 mg,(Young and Gauthier 1981), which is an amount capable of improving mood and cognitive function, reducing anxiety, and helping to achieve better sleep. Tryptophan achieves this by increasing the release of melatonin. Melatonin helps facilitate restful sleep, shortening the time it takes to get to sleep, increas- ing average duration of sleep, and improving sleep quality.(Shell, Bullias et al. 2010; Silber and Schmitt 2010)

Although its reputation was marred by a single manufacturing malfunction that caused serious medical problems in a small group of people back in the mid-1990s, tryptophan is now back on the market and is backed by numerous studies supporting its benefits. Because it is a mild sedative, tryptophan, like other sleep medications, can reduce reaction time.(Silber and Schmitt 2010)

Post-thanksgiving Drowsiness: It’s how much you eat, not the turkey

While many people think it’s the tryptophan in turkey that makes people sleepy at Thanksgiving, the real culprit that leads to drowsiness may really just be the overeating that comes with this high- calorie meal. it’s been known for over 60 years that the tryptophan content of turkey is similar to both other meats in general and other poultry in particular.(greenhut, Potter et al. 1947)

Tryptophan is found in nearly all protein-based foods as well as many vegetables. it is abundant in dairy products (milk, yogurt, cottage cheese), sweets (chocolate, dried dates), grains (oats) and meats (red meat, eggs, fish, poultry), nuts and seeds (sesame, sunflower seeds, pumpkin seeds, and peanuts), and legumes (chickpeas, soybeans). among the foods with the highest amounts are eggwhites, atlantic cod, and spirulina.

Prescription Drugs

One of the fastest growing segments of the prescription drug market are sleep aids. These drugs are generally effective in making it easier to fall asleep, stay asleep, and increase total time asleep. There are, however, adverse affects, such as dependency, withdrawal, and tolerance. The World Health Organization broadly defines dependence as “the state of needing or depending on something or someone for support or to function or survive,” and as applied specifically to alcohol and other drugs, “a need for repeated doses of the drug to feel good or to avoid feeling bad.” Withdrawal symptoms are generally defined as those that start after a drug is discontinued or reduced (i.e. symptoms not present before treatment). Tolerance is defined as a decrease in a drug’s effect with continued administration, which results in the need to increase the dose of the drug.(World Health Organization 2010)

not all users of hypnotics become dependent, tolerant, or expe- rience withdrawal. There are various strategies, such as intermittent use, that can minimize adverse effects. It’s important to evaluate the potential benefits and risks with your doctor before beginning any prescription sleep drug program. However, because many sleep-aid drugs can cause side-effects, it’s worthwhile to improve sleep hygiene and work with other exercise, relaxation, or natural medicine ap- proaches before going the sleep medication route.

PUTTING IT ALL TOGETHER

Several key points emerge from our systematic review of the re- search on human sleep patterns:

» Sleep is essential to health. Optimal functioning of almost every body system requires sleep.

» The body needs to be re-synchronized on a daily basis through food, exercise, and face-to-face interaction with other peo- ple. Benjamin Franklin’s saying, “early to bed, early to rise…”, and what your grandmother told you about frequent exercise and regu- lar mealtimes are all true and supported by very recent research.

» Prescription medications, while helpful on an occasional or short-term basis, can have unwanted consequences that include the “rebound effect,” where sleep becomes worse after stopping the use of medication.

» Avoiding information overload is helpful, particularly in the evening.

» Helping the body get in the right mood for sleep is essen- tial, like an airplane taking the proper approach to landing.

» Sleep is a body function most people can’t consciously con- trol, but the way you treat yourself during the day can have a direct impact on whether your body can achieve good sleep at night.

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A Daily Dilemma
We make thousands of decisions every day, big and small. In terms of medical diagnosis and treatment, these decisions can have profound implications for a patient’s future health and longevity: “Which treatment do I choose?”, “Do those test results mean I should change my treatment?” and “Is eating that bacon a bad idea?” While each of these decisions are often influenced by factual medical data, the way in which this information is interpreted and presented can often be unclear or misleading.

How information is reported: bad writing, bad reporting
Many people correctly perceive that the quantity of available medical information is overwhelming. Thus it’s often desirable to have a succinct summary of a medical report that gives the purpose, approach, and result of the study in question. The abstract (summary) section of a published research article fulfills this purpose and is the section that is most likely to be read. But up to a third of the abstracts of medical studies “contain data that were either inconsistent with corresponding data in the article’s body (including tables and figures) or not found in the body at all,” even in major medical journals. Reading the full text of a study can usually clear up these discrepancies, but often requires significant time and experience to read and interpret.

Who’s paying for the research?
It has long been known that trials funded by a drug manufacturer are often biased.(Barden, Derry et al. 2006) C. Seth Landerfield, a researcher from the University of California at San Francisco, found that among abstracts presented at a national medical society, industry support increased by 30-fold the odds that the result of a study would be favorable to the drug being researched.(Landefeld 2004)

Medical sensationalism
It should perhaps not come as a surprise that this financial bias is often not acknowledged by news media reporting on the results of clinical studies.(Hochman, Hochman et al. 2008) Media reports, perhaps in their zeal to grab attention with a great headline, often fail to mention important facts about studies on which they report. A review of 187 media reports found that 34% did not mention study size, 53% did not mention or were ambiguous about the study design, 40% did not quantify the main result, and only 29% mentioned the possibility of side effects.(Woloshin and Schwartz 2006) Given these problems in reporting the results of research, it’s often difficult to answer fundamental questions such as, “When is a number a correct number?” and “When is a number an important number?”

The bias effect of commercial funding extends even further, and can include the prescribing of medications. Much of the educational prescribing information being read by medical providers, and the lavish conferences where they learn about these medications, are also funded by major pharmaceutical manufacturers.(Rutledge, Crookes et al. 2003) Fortunately, efforts are underway to avoid commercial funding bias in the way drug information is presented to medical students.(McMahon, Neubauer et al. 2003) For example, both researchers and the World Health Organization have begun to issue calls for the establishment of independent grant-making institutes for funding pharmaceutical research.(Hardon 2003)

Math and medical literacy
All too often, one hears the phrase “I’m not good at math.” Nevertheless, medical writing is also a type of writing, and should follow basic principles of clarity and common sense. A well-written medical article is well-presented and clear to understand because the authors avoid using too much technical jargon.

A considerable amount of research has been published that focuses not only on how research should ideally be presented, but also on how well readers actually understand what they’re reading (this is especially important among those who should know how to read research, such as practicing clinicians). Whether patient or doctor, the issue of math illiteracy is unfortunately very common and can significantly undermine the process of informed decision making.(Gaissmaier and Gigerenzer 2008) The results of a medical study on treatment effectiveness, for example, are apparently much better understood when the results are presented as frequencies (e.g. “4 out of 5 people”) rather than as probabilities (e.g. “80%”). Although the difference might seem trivial or obvious, the way research is presented is important and can be an example of “when framing influences judgement.”(Gigerenzer 2003)

Closely related to math literacy is fundamental medical literacy. There is a substantial volume of information involved in any domain of medical care, and patients diagnosed with rare medical conditions often find themselves knowing more about their conditions than some of the medical providers with whom they consult. This is understandable, as who would be more motivated than the person diagnosed with the medical problem in question? This has been confirmed by researchers conducting a study on basic medical knowledge, who examined a concept they called the “minimum medical knowledge” needed to understand typical signs and/or risk factors of common medical problems such as heart attack, stroke, chronic obstructive pulmonary disease, and HIV/AIDS. They found that people with a university degree, some medical background, or personal illness experience had only a moderately higher “minimum medical knowledge” than those without these advantages. Among other things, this suggests that no one person can possibly have all the answers, and should have the effect of encouraging patients in a medical consultation to ask questions about their diagnosis and treatment.

Am I like those people?
When considering the results of a medical study, it is important to ask questions about whom the study included as volunteers. Clinical trials often select a very narrow group of volunteers to participate; quite often the age, gender, or other important criteria of clinical trial volunteers are not representative of the general population, nor of a specific individual considering a healthcare decision that may require information based on research.

In a strident call for equality in research, Dr. Somnath Saha, a researcher at the Portland VA Medical Center, has pointed out “a historical bias favoring white men.” As with most other institutions in the United States, medical research no longer actively excludes women and minorities. But the history of these institutions, the way they were designed and built – predominantly by and for white men – slants them in a way that continues to limit access for other groups.”(Saha 2009) Dr. Saha is careful to point out that “the distrust of research is usually applied to the research enterprise – the people and institutions carrying out research – not to the concept of research per se.” People want the results of research, but they expect it to be conducted in a rational and sensible way.

Simple tools for presenting information clearly
With the vast sums of money being spent on medical research, it’s reasonable to expect that a considerable amount of time and effort would be spent making sure the results are clear and well-presented. Although this is not always the case, there is hope. For the past twenty years, Edward Tufte has been writing books advocating clear communication of information reporting, which include Visual Explanations, Envisioning Information, The Visual Display of Quantitative Information, and Data Analysis for Politics and Policy. These principles have slowly begun to contribute to improvements in the clarity with which results of medical research are presented.(De Amici, Klersy et al. 1997)

Another important contributor to clearer scientific literacy is Gerd Gigerenzer of the Max Planck Institute for Human Development in Germany, who has written numerous tutorials for researchers suggesting how to clearly present written information. One such paper, addressing the theme of how doctors can “improve the presentation of statistical information so that patients can make well informed decisions,” is available on our website.(Gigerenzer and Edwards 2003)

Why is this important?
In the context of a clinical visit, a process of shared decision-making often leads to higher satisfaction with the visit.(Mathieu, Barratt et al. 2007; Nagle, Gunn et al. 2008) In order for that process to be effective, beneficial, and truly shared, it’s important that the information being used is understandable by both patient and practitioner alike.(Hoffrage, Lindsey et al. 2000; Gigerenzer and Edwards 2003)

Guidelines for evaluating research results for yourself
In evaluating the quality and reliability of medical research, the ideal is information that is objective and unbiased, so that we know the pros and cons of a particular test or treatment will be clear. Medical studies are reported first in the primary scientific literature (conferences or journals) and second in the general media. Most people will typically hear of a study first in the general media. Here are some pointers for weighing that information:

» Is the article’s headline or writing presented in a sensationalized way that might serve to discount essential weaknesses or disadvantages of the study results?

» Does the article provide background information that is helpful in evaluating whether the new finding is relevant or important? For example, does the article address what’s already known about the topic and whether this new study represents progress or provides new cautions?

» Does the article being presented relate in some way to advertisers associated with the show, publication, or website? Is the article identified as an advertisement?

» Is the news presented in a balanced way that also highlights the new treatment’s side effects? Are alternate points of view presented in interviews with other researchers or clinicians?

When reading the original results of a study, for example in a medical journal, here are some additional guidelines to assess the usefulness of that information:

» What type of study is it: laboratory or cell culture, animal, or human? The results of laboratory and animal research do not always translate into success in treating people.

» Was the article presented at a meeting or published in a peer-reviewed medical journal? Although meeting results are more current, treatments reported at conferences have not yet been subjected to as much scrutiny as would be done in a journal. If results are posted on the investigator’s web site or in a company’s brochure, the same caution is justified.

» Who conducted the study? Although researchers at well-known universities or research groups are typically considered to be more objective than individuals without institutional affiliations, this is by no means always the case. Many questionable relationships between university-based research programs and their funding sources have been reported. These relationships are often difficult to assess or clearly understand.

» How was the study funded? Funding from government, independent grant agencies, or foundations that rely on a peer-reviewed selection process to critically evaluate and select studies to be funded are preferred. Ideally, commercial sponsorship of research will be disclosed in the publication.

» How large was the study? Of the people originally recruited, how many completed the trial? Results of small studies do not always accurately predict how well the treatment or test will perform in larger groups of people.

» Who were the people who volunteered for the study, in terms of age, sex, ethnic group, medical history, etc.? This is important in extrapolating the results to a specific person.

» Is this a new treatment being first reported or has the approach been tested by other researchers as well? Results that are validated by repeat trials tend to be more reliable.

» In drug trials, were side effects mentioned and, if so, how do potential side effects compare to the potential benefits?

Other useful study details to consider
Components of study design that help research conform to these parameters include randomization and blinding. Typically, randomized trials will provide more reliable results. When participants are randomized to control groups (measuring the known medication or procedure) and treatment groups (comparing the know medication or procedure to either a new medication, a new procedure, an herbal formula, etc.), we are assured of a selection process that is not resulting from an individual’s or an institution’s biases. Similarly, when study volunteers (a “Single Blinded” study) or both the volunteers and the researchers themselves (“Double Blinded”) don’t know which group participants are assigned to, this further helps avoid bias and typically produces more useful results.

Some other types of studies you may be reviewing include cross-sectional studies, which take place at a single point in time (such as estimating how many people in the city of Seattle currently have ovarian cancer), versus a longitudinal study, which involves a series of measurements taken over a long period of time (such as following a group of smokers for 10 years to see who develops cancer). Cross-sectional studies examine the relationship between different variables at a fixed point in time. However, since exposure and disease status are measured at the same point in time, it may not always be possible to distinguish whether the exposure preceded or followed the disease. A “cohort study,” where a group is identified before the appearance of the disease that is under investigation, is often undertaken to obtain evidence to try to refute the existence of a suspected association between cause and disease. Results that are obtained from long-term cohort studies are considered to be higher quality studies than retrospective or cross-sectional studies.

Summary
As with any human endeavor, there is a wide range of quality and validity in the arena of medical research. Fortunately, in evaluating research results, the principles of what constitutes good research are easily accessible. We hope that the guidelines and perspectives raised in this article will be helpful to you in considering the veracity and relevance of medical information to your particular question.

References
Barden, J., S. Derry, et al. (2006). “Bias from industry trial funding? A framework, a suggested approach, and a negative result.” Pain 121(3): 207-18.

De Amici, D., C. Klersy, et al. (1997). “Graphic data representation in anaesthesiological journals: a proposed methodology for assessment of appropriateness.” Anaesth Intensive Care 25(6): 659-64.

Gaissmaier, W. and G. Gigerenzer (2008). “Statistical illiteracy undermines informed shared decision making.” Z Evid Fortbild Qual Gesundhwes 102(7): 411-3.

Gigerenzer, G. (2003). “Why does framing influence judgment?” J Gen Intern Med 18(11): 960-1.

Gigerenzer, G. and A. Edwards (2003). “Simple tools for understanding risks: from innumeracy to insight.” Bmj 327(7417): 741-4.

Hardon, A. (2003). “New WHO leader should aim for equity and confront undue commercial influences.” Lancet 361(9351): 6.

Hochman, M., S. Hochman, et al. (2008). “News media coverage of medication research: reporting pharmaceutical company funding and use of generic medication names.” Jama 300(13): 1544-50.

Hoffrage, U., S. Lindsey, et al. (2000). “Medicine. Communicating statistical information.” Science 290(5500): 2261-2.

Landefeld, C. S. (2004). “Commercial support and bias in pharmaceutical research.” Am J Med 117(11): 876-8.

Mathieu, E., A. Barratt, et al. (2007). “Informed choice in mammography screening: a randomized trial of a decision aid for 70-year-old women.” Arch Intern Med 167(19): 2039-46.

McMahon, B. J., R. Neubauer, et al. (2003). “Developing and implementing a program of grand rounds for internists that is free of commercial bias.” Ann Intern Med 139(1): 77-8.

Nagle, C., J. Gunn, et al. (2008). “Use of a decision aid for prenatal testing of fetal abnormalities to improve women’s informed decision making: a cluster randomised controlled trial [ISRCTN22532458].” Bjog 115(3): 339-47.

Pitkin, R. M., M. A. Branagan, et al. (1999). “Accuracy of data in abstracts of published research articles.” Jama 281(12): 1110-1.

Rutledge, P., D. Crookes, et al. (2003). “Do doctors rely on pharmaceutical industry funding to attend conferences and do they perceive that this creates a bias in their drug selection? Results from a questionnaire survey.” Pharmacoepidemiol Drug Saf 12(8): 663-7.

Saha, S. (2009). “Rectifying institutional bias in medical research.” Arch Pediatr Adolesc Med 163(2): 181-2.

Woloshin, S. and L. M. Schwartz (2006). “Media reporting on research presented at scientific meetings: more caution needed.” Med J Aust 184(11): 576-80.

Click here to read this entire article on PubMed.

When oxidative stress levels are reduced in cancer cells, their growth is more easily controlled through a process called apoptosis. During apoptosis, cells are removed by the immune system before they lose their cell wall, thus avoiding an inflammatory response to the dying cells.
However, when oxidative stress levels go up, cancer cell death happens through a slower, messier, and less effective pathway called pyknosis or necrosis. Additionally, the ability of the body to “clean up” the resulting cellular debris from cancer cell death is also inhibited by oxidative stress. The body’s house-cleaning cells (called monocyte-derived macrophages) cannot function optimally under conditions of oxidative stress (i.e. low oxygen levels).

The authors of the above-mentioned study on Burkitt lymphoma cells and chemotherapy suggest that including antioxidants in the treatment protocol may enhance chemotherapy-induced apoptosis and phagocytosis. (Shacter, Williams et al. 2000) A second study, involving the chemotherapy drugs etoposide and calcimycin, confirms this finding: Human Burkitt’s lymphoma cells were unable to die quickly by apoptosis in the presence of oxidative stress and instead died using the slower and messier method of necrosis. In this study, it was found that oxidative stress inhibited apoptosis by depleting cells of their energy source, which is called adenosine triphosphate (ATP). (Lee and Shacter 1999)

Related to these observations about the relationship between cellular oxidative stress levels is the widely held view in medicine that the use of antioxidant dietary supplements diminishes chemotherapy’s effectiveness. However, when one looks more closely at the existing published science on how antioxidants and chemotherapy combine, the true answer is not so definitive. Many research studies, encompassing cell culture tests in the laboratory and also animal and some human studies, are coming to a conclusion often very different from the conventional perspective that chemotherapy and antioxidants should never be combined.

One example is a human study in which researchers discovered that higher levels of the antioxidant selenium in the blood of patients with aggressive B-cell non-Hodgkin’s lymphoma correlated with increased achievable doses of anthracycline based chemotherapy, better treatment response, achievement of long term remission, and longer overall survival. It is important to note that in this study, however, the level of selenium present in the blood of patients was from their diet; the study was not a test of supplemented selenium. (Last, Cornelius et al. 2003) As seen in this study, higher levels of natural antioxidants can help treatment outcomes.

On the other hand, the decreased levels of antioxidants (or oxidative stress) that are caused by many chemotherapy treatments correlates with increased side effects. In patients with Hodgkin’s lymphoma, chemotherapy with Adriamycin, bleomycin, vincristine, and dexamethasone significantly decreases antioxidant levels. (Kaya, Keskin et al. 2005) In children with acute lymphoblastic leukemia who received high-dose methotrexate, oxidative damage to proteins as well as other factors was related to toxic side effects. (Carmine, Evans et al. 1995)

Using antioxidants during chemotherapy is an important and controversial question among health care providers, patients, and their support teams. In previous issues of Avenues, we have researched this subject thoroughly for prostate, breast, lung, colon, and ovarian cancers. In this article, we turn our focus to lymphoma, conducting a systematic search for published research that would support or discourage the use of antioxidants in combination with chemotherapy. The overwhelming majority of studies find a favorable interaction between antioxidants and chemotherapy, providing evidence that antioxidants can decrease chemotherapy side effects, increase treatment effectiveness, and decrease resistance to chemotherapy.

For this paper, we searched for clinical or laboratory data published in peer-reviewed medical journals, conducted by cancer researchers in universities and medical research facilities around the world. Some of these studies are still in early stages and include only laboratory or animal data while others have advanced to include human volunteers. We organized these data into the major categories of specific chemotherapy drugs. Within each section for a specific drug are found the research on combinations of that drug with various antioxidants, grouped by the name of the antioxidant in alphabetical order. We also point out specifically which studies were conducted in a laboratory (i.e. used cancer cell cultures), used animals, or involved human volunteers. As each antioxidant appears in the paper for the first time, we provide some introduction to the antioxidant including what food sources naturally contain it, other common applications in clinical use, and typical dosages. The dosages given are not necessarily appropriate for all patients and should be individualized with practitioner guidance.

Bendamustine

CURCUMIN
Curcumin is a polyphenol and is an extract of the Indian curry spice plant turmeric. Curcumin is known for its anti-tumor, antioxidant, anti-amyloid, and anti-inflammatory properties. It also promotes healthy bile excretion and healthy platelet function.

» Curcumin: The best supplements contain curcumin at 75% or higher concentration. Typical doses range from 500 mg to 2,000 mg daily. Take with meals, as curcumin can cause stomach upset when taken on an empty stomach. Bioavailability and potency are increased when combined with Bioperine, an extract from black pepper.

In non-Hodgkins lymphoma cells (not cell cultures, but rather cells taken directly from bone marrow of patients), curcumin increased bendamustine treatment effect, likely due to NF-KappaB inhibition by curcumin. (Alaikov, Konstantinov et al. 2007)

Cisplatin

TEMPOL & MNTBA
Tempol is an antioxidant drug that is used to prevent hair loss for cancer patients undergoing treatment. MnTBA is a synthetic antioxidant.

When combined with Tempol or MnTBA, cisplatin was found to induce cell death in human B lymphoma cells without any detectable oxidative stress. Furthermore, there was no inhibition of the ability of cisplatin to destroy cancer cells. (Senturker, Tschirret-Guth et al. 2002)

COMBINATIONS TO AVOID:
CISPLATIN WITH N-ACETYL CYSTEIN
In human B lymphoma cells, N-acetyl cysteine inhibited cisplatin induced cell death, but not because of interference with oxidative stress. (Senturker, Tschirret-Guth et al. 2002) N-acetyl cysteine is known to inactivate cisplatin and also decrease absorption of cisplatin into cancer cells cell. (Kroning, Lichtenstein et al. 2000)

Cyclophosphamide

METHYLSELENINIC ACID (MSA)
Methylseleninic Acid is an organic selenium compound, produced by the body’s metabolism of the mineral selenium found in foods. Brazil nuts are the single best food source of selenium. Selenium is as an antioxidant most widely known as a cancer preventive.

» Selenium (mineral): The US adult Tolerable Upper Intake Level (UL) is 400 micrograms a day and the Lowest Observed Adverse Effects Level (LOAEL) for adults is about 900 micrograms daily. There are several different forms of selenium. Se-Methylselenocysteine is a highly bioavailable form because it is not incorporated within a protein such as the form selenomethionine. We recommend getting selenium either in the organically bound forms, such as of Se-Methylselenocysteine, or a combination of selenium compounds with L-selenomethionine, sodium selenate, selenodiglutathione, and Se-methylselenocysteine.

MSA increased the chemotherapeutic effect of cyclophosphamide in human B-cell lymphoma cells. Cell lines were either sensitive or resistant to MSA. Treatment effect of cyclophosphamide was increased from 19% (cyclophosphamide alone) to 50% (cyclophosphamide with MSA) in sensitive cells and from 7% (alone) to 22% (with MSA) in resistant cells. (Juliger, Goenaga-Infante et al. 2007)

SULFOETHYL GLUCAN
Sulfoethyl-glucan is a beta-1,3-D-glucan derivative from the baker’s yeast Saccharomyces cerevisiae. Besides stimulating the immune system, it has high antioxidant and antimutagenic activity (reduces damage to DNA). (Krizkova, Durackova et al. 2003)

» Beta-1,3 D-glucan: Typical dosages range from 100 to 500 mg per day.

Sulfoethyl glucan derived from yeast polysaccharide enhanced the effect of cyclophosphamide in mice with lymphosarcoma both sensitive and resistant to chemotherapy. (Khalikova, Zhanaeva et al. 2005; G, M et al. 2008)

RETINOIDS & MELATONIN
Retinoids are vitamin A derivatives. Vitamin A (retinol) is a fat-soluble, antioxidant vitamin important for bone growth and vision. Vitamin A is ingested in a precursor form from animal foods and is especially plentiful in cod liver oil. Other good sources include butter and egg yolks as well as whole milk, cream, and yogurt.

» Vitamin A: Typical dosages range from 2500 IU to 25,000 IU.

Melatonin is a hormone that is released from the pineal gland in the evening and promotes normal sleep; its secretion diminishes significantly with age. It is known to help maintain cell health and many people take it to improve sleep. It is also known to reduce metastasis in cancer patients. In most published studies, melatonin shows a beneficial effect, although it has been reported that in a small proportion of people, melatonin can paradoxically cause sleep disturbance. In others, there can be residual daytime drowsiness, which is usually resolved by using a lower dose.

» Melatonin: Typical dosages range from 1 mg to 20 mg. If aiming for a high dosage, one should start with 1 mg and increase the dosage slowly by 1 mg every 3 to 7 days. The ideal is to achieve peak blood levels of melatonin at about 2 am. To do so, one can take the melatonin at bedtime, ideally between 9 pm and 10 pm.

Twenty patients with stage III or IV low-grade non-Hodgkin’s lymphomas received one month of treatment with cyclophosphamide, somatostatin, bromocriptine, retinoids, melatonin, and ACTH (Adrenocorticotropic hormone).

Somatostatin is a naturally occurring hormone (which may be given as a prescription drug) that inhibits the release of growth hormone (GH, somatotropin) and thyroid-stimulating hormone (TSH). Bromocriptine is a drug used in the treatment of pituitary tumors and Parkinson’s disease and is a dopamine agonist.

This treatment was continued if patients had stable or responding disease. After one month, 70% of patients had a partial response, 20% had stable disease, and 10% progressed during treatment. Of the 70% of patients who had a partial response, none had disease progression (average follow up time was 21 months) and 50% of these patients had a complete response. Of the 20% of patients who in the first month of treatment had stable disease, 25% had a partial response and 75% progressed on therapy. Toxicity was mild and included drowsiness, diarrhea, and hyperglycemia. (Todisco, Casaccia et al. 2001)

In a case report, a patient who experienced a relapse of high-grade non-Hodgkin lymphoma two years after autologous stem cell transplant was treated with cyclophosphamide, somatostatin, bromocriptine, retinoids, melatonin, and ACTH (Adrenocorticotropic hormone). Side effects were minimal and the patient was able to continue normal activities. After two months of treatment, the patient had a partial response and after five months, a complete response. At the time the case report was written, the patient was in complete remission 14 months after beginning treatment. (Todisco 2006)

In a second case report, a patient with stage IV low grade non-Hodgkin lymphoma was treated with cyclophosphamide, somatostatin, bromocriptine, retinoids, and melatonin. Side effects were minimal and the patient was able to continue normal activities. After two months of this treatment, he had a partial response and after five months a complete response. At the time of the case report, 18 months after beginning treatment, the patient was in complete remission. (Todisco 2007)

Doxorubicin

COENZYME Q10 (COQ10)
CoQ10 is naturally produced in the body and is necessary for the basic functioning of cells. CoQ10 is also found in dietary sources such as fish, meat, spinach, broccoli, peanuts, and whole grains. It is a vitamin-like substance that can also act as an antioxidant. Among other functions, it is incorporated into the mitochondria of cells throughout the body and facilitates and regulates the transformation of fats and sugars into energy. Patients with heart problems often use CoQ10.

» CoQ10: Dosages range from 15 mg to 600 mg per day.

Twenty children with acute lymphoblastic leukemia or non-Hodgkin lymphoma were treated with anthracycline chemotherapy (this family of drugs include doxorubicin and daunorubicin, among others). Heart related side effects are a major concern with anthracycline chemotherapy, so ten of these children also received CoQ10 to test the ability of CoQ10 to protect the heart. The children receiving CoQ10 experienced less cardiac effects than the children receiving no CoQ10. Percentage left ventricular fractional shortening decreased more in children not taking CoQ10. Interventricular septum wall thickness decreased only in children who did not take CoQ10 and abnormalities of the septum wall motion was similarly only detected in children not taking CoQ10. Overall this study found a protective effect of taking CoQ10 with anthracycline chemotherapy. (Iarussi, Auricchio et al. 1994)

METHYLSELENINIC ACID (MSA)
MSA increased the chemotherapeutic effect of doxorubicin in human B-cell lymphoma cells. Cell lines were either sensitive or resistant to MSA. Treatment effect of doxorubicin was increased from 21% (doxorubicin alone) to 49% (doxorubicin with MSA) in sensitive cells and from 8% (alone) to 44% (with MSA) in resistant cells. A 50% reduction of NF-kappaB activity was seen after exposure to MSA, perhaps one of the mechanisms by which MSA works synergistically with chemotherapy. (Juliger, Goenaga-Infante et al. 2007)

VITAMIN B6 (PYRIDOXINE)
Vitamin B6 comes from a variety of dietary sources, such as turkey, tuna, spinach, banana, lentils, and potatoes.

» Vitamin B6: Typical doses range between 10 mg and 200 mg per day. Individuals using more than 100 mg per day for more than two months should be supervised by a health care professional, as chronic overdose may lead to sensory neuropathy.

To test if vitamin B6 could help prevent palmar-plantar erythrodysesthesia (PPES) or hand-foot syndrome, an animal study (randomized, double-blinded clinical trial) included forty-one dogs with non-Hodgkin lymphoma that received Doxil chemotherapy. Doxil is a drug that is made by placing doxorubicin into a fat bubble called a liposome. The dogs were randomized to receive either oral vitamin B6 or placebo daily during Doxil chemotherapy (total of five Doxil treatments of 1 mg/kg i.v. every 3 weeks). Vitamin B6 did not completely prevent hand-foot syndrome in the dogs, however it decreased the risk of serious hand-foot syndrome and therefore prevented dose reduction or discontinuation of Doxil therapy. Dogs receiving vitamin B6 came close to the cumulative target dose of Doxil at a median dose of 4.7 mg/kg (compared to the target dose of 5 mg/kg). Dogs receiving placebo were only able to tolerate a median dose of 2.75 mg/kg. There was a trend toward longer remission length in the dogs receiving vitamin B6 likely because they were able to receive more Doxil without delays or discontinuation of treatment. (Vail, Chun et al. 1998)

Etoposide

N-ACETYL CYSTEINE, TEMPOL, & MNTBAP
N-acetyl cysteine is an efficiently absorbed and used form of the amino acid L-cysteine. L-cysteine, L-glutamic acid, and glycine are the three amino acids that form glutathione, which is one of the most important and powerful antioxidants in the body.

» N-acetyl cysteine: Typical dosages range between 600 mg and 1,800 mg per day.

Etoposide was found to induce cell death in human B lymphoma cells without any detectable oxidative stress. Furthermore, the antioxidants N-acetyl cysteine, Tempol, and MnTBAP did not inhibit Etoposide induced cell death. (Senturker, Tschirret-Guth et al. 2002)

GREEN TEA EXTRACT – EPIGALLOCATECHIN-3-GALLATE (EGCG)
Epigallocatechin-3-gallate (EGCG) is the principal polyphenol (a group of antioxidants) found in green tea.

» EGCG: One cup of green tea contains between 10 mg and 400 mg of polyphenols depending on the source, amount of leaves used, and steeping time. EGCG may be conven2iently obtained from extracts. Among the green tea extract dietary supplement products, a desirable potency is standardized to 98% polyphenols, 45% of which is EGCG.

In a lymphoma cell line called B-lymphoblastoid Ramos, EGCG enhanced the chemotherapeutic effect of etoposide. (Noda, He et al. 2007)

METHYLSELENINIC ACID (MSA)
MSA increased the chemotherapeutic effect of etoposide in human B-cell lymphoma cells. Cell lines were either sensitive or resistant to MSA. Treatment effect of etoposide was increased from 32% (etoposide alone) to 60% (etoposide with MSA) in sensitive cells and from 4% (alone) to 22% (with MSA) in resistant cells. (Juliger, Goenaga-Infante et al. 2007)

Methotrexate

VITAMIN A
In a prospective randomized un-blinded clinical trial, vitamin A was given with high-dose-methotrexate to children with leukemia and lymphoma to see if vitamin A could protect against chemotherapy induced intestinal malabsorption. Thirty five children participated in the trial. Twenty-two patients received a single dose of 180,000 IU before methotrexate chemotherapy and thirteen patients received chemotherapy only. There was no difference in blood, skin, and organ toxicities. Intestinal absorption was significantly better in children receiving vitamin A. Absorption was decreased in only five of twenty-two (23%) children receiving vitamin A, compared to eight of thirteen (62%) children receiving chemotherapy only. Therefore, this study found some benefit to vitamin A treatment to prevent mucosal damage and therefore malabsorption in the intestines. (Dagdemir, Yildirim et al. 2004)

Rituximab

Rituximab is a newly-developed antibody therapy, not a traditional chemotherapy.

BETA-1,3 D-GLUCAN
Beta-1,3 D-glucan is derived from yeast and is a macrophage stimulator. Macrophages are an important part of the immune system.

» Beta-1,3 D-glucan: Typical dosages range from 100 mg to 500 mg per day.

In an animal study with mice, some of which had non-Hodgkin’s lymphoma and some Hodgkin’s lymphoma, the combination of rituximab and beta-1,3 D-glucan was significantly more effective than either rituximab or beta-glucan treatment alone. Mice with widespread lymphoma had significantly increased survival in the mice receiving the combination of rituximab and beta-glucan. No toxicity due to the combination was observed. (Modak, Koehne et al. 2005)

Cyclophosphamide, Vincristine, & Doxorubicin

L-CARNITINE
L-carnitine is an antioxidant that comes from protein-rich dietary sources such as red meat and dairy. L-carnitine helps convert fatty acids into energy; as a supplement, it is used among other things for increased energy, heart health, and age related memory loss (Acetyl-L-carnitine is preferred for memory). Although often used for weight loss, no clinical evidence has emerged that supports effectiveness for this application.

» L-carnitine: Typical doses range from 300 mg to 4000 mg. If using high doses, taking half the dose twice daily is beneficial.

In a clinical trial, L-carnitine was given to investigate if it could reduce cardiotoxicity from chemotherapy. Twenty patients received 3 g of L-carnitine intravenously before each chemotherapy cycle, followed by 1 g of L-carnitine orally per day for 21 days. Another twenty patients received placebo. Chemotherapy consisted of six CHOP cycles (cyclophosphamide 750 mg/m2 in 500 mL NaCl, vincristine 1.4 mg/m2, max. 2 mg absolute; doxorubicin 50 mg/m2 in 259 mL NaCl; days 2–5: prednisolone 100 mg p.o.). Cumulative doxorubicin doses of up to 600 mg/m2 were reached in this study. No cardiotoxicity occurred in either group. Survival, quality of life, and duration of remission was the same in both groups. Thus this study found no adverse effect of L-carnitine on effectiveness of chemotherapy. (Waldner, Laschan et al. 2006)

In a previous study, fifteen cancer patients receiving doxorubicin treatment had increased cardiac abnormalities with higher cumulative doses of doxorubicin. A trend towards lower serum carnitine levels was also observed with higher cumulative doses of doxorubicin, which was what led the study authors to consider investigating the role of carnitine in prevention of cardiac side effects. (Yaris, Ceviz et al. 2002)

GENISTEIN
Genistein is an isoflavone found in legumes, especially soybeans. Isoflavones are antioxidants that counteract the damaging effects of free radicals in body tissues. Isoflavones such as genistein also have anti-angiogenic effects, blocking the formation of new blood vessels needed to support the growth of tumors.

» Genistein: A good product will use organic non-GMO genistein. To achieve anti-tumor effects, the target daily dose, based on animal studies and calculations for similar human dosage, is 1,500 mg. The recommended dose for further research is between 100 mg and 1,100 mg. (Boik 2001) One cup of soy milk will contain on average about 45 mg of genistein and the other related isoflavones.

In mice with large cell lymphoma, the CHOP chemotherapy regimen was given along with genistein (genistein was given for 5 days before CHOP). The combination of CHOP and genistein led to greater tumor growth inhibition than CHOP alone. The tumor growth was delayed 17 days in mice given the combination of genistein and CHOP and only 8 days in mice given CHOP alone. Genistein decreased NF-kappaB and increased the Bax/Bcl-2 ratio. (Mohammad, Al-Katib et al. 2003)

CONCLUSIONS
The 23 studies reviewed in this article provide compelling evidence suggesting that the question of chemotherapy in combination with antioxidants in the treatment of lymphoma deserves reconsideration, further discussion, and further research. We have reviewed cell culture, animal, and human clinical studies. It is important to note that 22 of these 23 studies identified either beneficial outcomes to combining antioxidants with chemotherapy or provided evidence dispelling the assumption that increased oxidative stress is required for chemotherapy to be effective. Although these studies are not conclusive, they nevertheless provide a basis for re-examining the long-held assumption that antioxidants are always contraindicated in the context of chemotherapy treatment for lymphoma.

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REFERENCES

Alaikov, T., S. M. Konstantinov, et al. (2007). “Antineoplastic and anticlastogenic properties of curcumin.” Ann N Y Acad Sci 1095: 355-70.

Carmine, T. C., P. Evans, et al. (1995). “Presence of iron catalytic for free radical reactions in patients undergoing chemotherapy: implications for therapeutic management.” Cancer Lett 94(2): 219-26.

Dagdemir, A., H. Yildirim, et al. (2004). “Does vitamin A prevent high-dose-methotrexate-induced D-xylose malabsorption in children with cancer?” Support Care Cancer 12(4): 263-7.

G, K., P. M, et al. (2008). “Yeast cell wall polysaccharides as antioxidants and antimutagens: Can they fight cancer?” Neoplasma 55(5): 387-93.

Iarussi, D., U. Auricchio, et al. (1994). “Protective effect of coenzyme Q10 on anthracyclines cardiotoxicity: control study in children with acute lymphoblastic leukemia and non-Hodgkin lymphoma.” Mol Aspects Med 15 Suppl: s207-12.

Juliger, S., H. Goenaga-Infante, et al. (2007). “Chemosensitization of B-cell lymphomas by methylseleninic acid involves nuclear factor-kappaB inhibition and the rapid generation of other selenium species.” Cancer Res 67(22): 10984-92.

Kaya, E., L. Keskin, et al. (2005). “Oxidant/antioxidant parameters and their relationship with chemotherapy in Hodgkin’s lymphoma.” J Int Med Res 33(6): 687-92.

Khalikova, T. A., S. Y. Zhanaeva, et al. (2005). “Regulation of activity of cathepsins B, L, and D in murine lymphosarcoma model at a combined treatment with cyclophosphamide and yeast polysaccharide.” Cancer Lett 223(1): 77-83.

Krizkova, L., Z. Durackova, et al. (2003). “Fungal beta-(1-3)-D-glucan derivatives exhibit high antioxidative and antimutagenic activity in vitro.” Anticancer Res 23(3B): 2751-6.

Kroning, R., A. K. Lichtenstein, et al. (2000). “Sulfur-containing amino acids decrease cisplatin cytotoxicity and uptake in renal tubule epithelial cell lines. ” Cancer Chemother Pharmacol 45(1): 43-9.

Last, K. W., V. Cornelius, et al. (2003). “Presentation serum selenium predicts for overall survival, dose delivery, and first treatment response in aggressive non-Hodgkin’s lymphoma.” J Clin Oncol 21(12): 2335-41.

Lee, Y. J. and E. Shacter (1999). “Oxidative stress inhibits apoptosis in human lymphoma cells.” J Biol Chem 274(28): 19792-8.

Modak, S., G. Koehne, et al. (2005). “Rituximab therapy of lymphoma is enhanced by orally administered (1–>3),(1–>4)-D-beta-glucan.” Leuk Res 29(6): 679-83.

Mohammad, R. M., A. Al-Katib, et al. (2003). “Genistein sensitizes diffuse large cell lymphoma to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy.” Mol Cancer Ther 2(12): 1361-8.

Noda, C., J. He, et al. (2007). “Induction of apoptosis by epigallocatechin-3-gallate in human lymphoblastoid B cells.” Biochem Biophys Res Commun 362(4): 951-7.

Senturker, S., R. Tschirret-Guth, et al. (2002). “Induction of apoptosis by chemotherapeutic drugs without generation of reactive oxygen species.” Arch Biochem Biophys 397(2): 262-72.

Shacter, E., J. A. Williams, et al. (2000). “Oxidative stress interferes with cancer chemotherapy: inhibition of lymphoma cell apoptosis and phagocytosis.” Blood 96(1): 307-13.

Todisco, M. (2006). “Relapse of high-grade non-Hodgkin’s lymphoma after autologous stem cell transplantation: a case successfully treated with cyclophosphamide plus somatostatin, bromocriptine, melatonin, retinoids, and ACT H.” Am J Ther 13(6): 556-7.

Todisco, M. (2007). “Low-grade non-Hodgkin lymphoma at advanced stage: a case successfully treated with cyclophosphamide plus somatostatin, bromocriptine, retinoids, and melatonin.” Am J Ther 14(1): 113-5.

Todisco, M., P. Casaccia, et al. (2001). “Cyclophosphamide plus somatostatin, bromocriptin, retinoids, melatonin and ACT H in the treatment of low-grade non-Hodgkin’s lymphomas at advanced stage: results of a phase II trial.” Cancer Biother Radiopharm 16(2): 171-7.

Vail, D. M., R. Chun, et al. (1998). “Efficacy of pyridoxine to ameliorate the cutaneous toxicity associated with doxorubicin containing pegylated (Stealth) liposomes: a randomized, double-blind clinical trial using a canine model.” Clin Cancer Res 4(6): 1567-71.

Waldner, R., C. Laschan, et al. (2006). “Effects of doxorubicin-containing chemotherapy and a combination with L-carnitine on oxidative metabolism in patients with non-Hodgkin lymphoma.” J Cancer Res Clin Oncol 132(2): 121-8.

Yaris, N., N. Ceviz, et al. (2002). “Serum carnitine levels during the doxorubicin therapy. Its role in cardiotoxicity.” J Exp Clin Cancer Res 21(2): 165-70.

Durante los últimos 25 años, los estadounidenses han estado durmiendo cada vez menos. [1] Los resultados de encuestas realizadas por la Fundación Nacional del Sueño [Nacional Sleep Foundation] muestran que el 69% de los adultos responden que tienen problemas para dormirse por lo menos varias veces a la semana, si no más. [2] El insomnio es el desorden del sueño más común en los Estados Unidos y afecta a cerca de 70 millones de personas; el 35% de los que contestaron a la encuesta respondieron que sufren de insomnio todas las noches y cerca del 60% respondieron que sufren de insomnio por lo menos varias noches a la semana.

El sueño fue descrito fisiológicamente en la década de 1930 [8] y aprendimos mucho al descubrir el movimiento rápido de los ojos [REM] en la década de 1950. [9] El sueño se divide generalmente en varias fases, determinadas por la actividad del cerebro durante la noche. Durante esas fases, nuestro cuerpo se repara y nuestros recuerdos se organizan.

Aunque todavía se desconocen las razones exactas por las cuales necesitamos el sueño, lo que queda claro es que la falta de sueño crónica puede tener serias consecuencias en contra de la salud. Hay evidencia creciente que sugiere que hay una relación entre el sueño y las funciones inmunológicas mucho más cercana de lo que se pensaba previamente. [2]

EL SUEÑO Y EL SISTEMA INMUNOLÓGICO
Cuando nos enfermamos, tendemos a sentirnos cansados y a dormir más. Pero, ¿es esto una coincidencia o es que el sueño cumple una función de recuperación inmunológica? En un estudio realizado con conejos a los que se les había inoculado una infección los que durmieron más, tuvieron una mejor recuperación. Esto sugiere que el sueño puede ayudar a recuperarse de una enfermedad. Sin embargo, en este estudio no quedó claro si había otros factores, como el estrés, que pudieran haber causado que los conejos que durmieron menos no mejoraran tanto. [2]

En los estudios con seres humanos hay una evidencia creciente que sugiere que la cantidad de sueño adecuado puede prolongar la vida; un estudio con pacientes ancianos demostró que la falta de sueño adecuado aceleraba significativamente la mortandad. [4]

Además, varios estudios han demostrado que la falta de sueño puede producir cambios en la actividad funcional de las células inmunológicas. En un estudio sobre el crecimiento de los tumores en las ratas, los tumores alcanzaron su tamaño máximo más rápidamente en los animales privados de sueño adecuado. [20]

A medida que aumentan los estudios en este tema, esperamos que pueda conocerse la naturaleza de la relación entre el sueño y el papel del sistema inmunológico en el control del crecimiento y tamaño de los tumores.

PÉRDIDA DE SUEÑO CRÓNICA VERSUS AGUDA
Se sabe que la pérdida de sueño crónica es dañina para los seres humanos, sin embargo cada vez hay más evidencia de que la interrupción ocasional del sueño puede ayudar al sistema inmunológico. [5, 6, 7]

En un estudio con ratas a las que se les había privado de sueño la capacidad de las ratas de defenderse de las infecciones dependió del tiempo que habían sido privadas de sueño. Como parte de la evolución, es posible que el sistema inmunológico necesite ser activado por breves períodos de ausencia de sueño, como los que ocurren cuando se está siguiendo perseguido por un predador. Pero la falta continuada de sueño hará que el sistema inmunológico termine fallando. [2]

COMO DORMIR MEJOR
La definición del “buen” sueño, es altamente subjetiva, pero la mayoría de las personas están de acuerdo en que un sueño de alta calidad consiste en quedarse dormido rápidamente, dormir toda la noche y levantarse sintiéndose revitalizado. Hay distintos modos de conseguir este tipo de sueño, unos tienen que ver con la conducta, otros con productos farmacéuticos.

MODOS COGNITIVOS Y DE CONDUCTA
Muchos estudios sugieren que a corto plazo “la conducta parece ser tan eficaz como los productos farmacéuticos” [22,23,24] y, en algunos casos “los resultados a largo plazo son mejores.”[25]

» Música: En un estudio reciente realizado por investigadores en Taiwán los resultados indican que quienes escuchan música suave y lenta a la hora de dormir “experimentan cambios físicos, como un ritmo más lento de la respiración y la circulación, que contribuyen al sueño tranquilo.” Durante 35 semanas los participantes escucharon 45 minutos de música sedante a la hora de ir a dormir. El estudio descubrió que como resultado “obtuvieron mejor calidad de sueño” y que “la calidad del sueño mejoró por semana, lo cual indica un efecto acumulativo.” [26]

» Yoga: Un estudio reciente muestra que los participantes que asistieron a sesiones de yoga regulares reportaron “mucho menos perturbación del sueño” que los miembros del grupo de control. Los resultados incluían mejor calidad del sueño, la habilidad de quedarse dormidos más rápidamente, duración mayor del sueño y menor uso de medicamentos para dormir. [27]

Ver más abajo “Sugerencias para la higiene del sueño” para encontrar otras estrategias para conseguir un buen sueño sin medicamentos.

MEDICAMENTOS: LA MELATONINA
La melatonina es una sustancia química que se logró aislar por primera vez en los laboratorios hace alrededor de unos 50 años [11,12]. Sus funciones se han relacionado con la regulación en el cuerpo de los ritmos diarios (circadiam) [13], los ritmos propios de las estaciones [14], las funciones inmunológicas [15] y la inhibición de tumores [10]. La melatonina no es un hipnótico ni un soporífico, sino que parece funcionar como una sustancia química que “le abre las puertas” al sueño, no algo que por sí mismo induzca al sueño.

La producción de melatonina ocurre en el cerebro y es regulada en su mayor parte por la luz ambiental. La mayor parte de la producción de melatonina ocurre en la oscuridad. La cantidad de melatonina producida por un individuo está determinada genéricamente, pero la edad también puede ser un factor, pues las personas tienden a producir menos melatonina a medida que aumentan en edad.

LA MELATONINA Y EL CÁNCER
Además de facilitar el sueño, algo que a su vez ayuda al sistema inmunológico, la melatonina también puede tener propiedades que ayudan a prevenir el cáncer al recoger del cuerpo a los radicales libres (que pueden dañar al DNA) [16] o que ayudan a retardar el crecimiento de tumores una vez que el cáncer se ha iniciado, y así contribuye a prolongar la vida cuando se la combina con las terapias convencionales. [19] Aunque mucho de esta investigación sólo se ha llevado a cabo en estudios con animales [10,18] estudios más recientes llevados a cabo con personas han dado resultados alentadores. [19]

En un estudio de 450 pacientes de cáncer avanzado con condiciones clínicas pobres o con tumores resistentes a la quimioterapia, “la melatonina pareció aumentar la respuesta al nivel del tumor, prolongó el tiempo de supervivencia y previno la neurotoxicidad ocasionada por la quimioterapia.”[28] Al envejecer tendemos a producir menor cantidad de melatonina, es posible que esto contribuya a la mayor incidencia de cáncer en los ancianos. Y si bien la melatonina no es una “cura” para el cáncer, sus propiedades justifican que se la siga estudiando.

MEDICAMENTOS: OTROS PRODUCTOS
Una de las áreas de mayor crecimiento de la industria farmacéutica son los medicamentos para dormir. Estos productos generalmente ayudan a quedarse dormido, a mantenerse dormido y aumentan el tiempo de sueño. Sin embargo, tienen efectos adversos como la dependencia, las dificultades experimentadas al dejar de tomarlas y la tolerancia.

La Organización Mundial de la Salud [World Health Organization] define la dependencia a un medicamento como “el desarrollo de un estado fisiológico que requiere la administración constante de un medicamento” para evitar dificultades al dejar de tomarlo. Estas dificultades aparecen por primera vez después de suspender o disminuir un medicamento (es decir son síntomas que no aparecían antes del tratamiento). La tolerancia se define como la disminución del efecto de un medicamento debido a la administración continuada, que crea la necesidad de aumentar la dosis. [24]

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SUGERENCIAS PARA LA HIGIENE DEL SUEÑO

DORMIR SÓLO CUANDO SE TIENE SUEÑO
Esto reduce el tiempo en que se está en la cama sin lograr conciliar el sueño. Si no logra dormirse en los primeros 20 minutos, levántese y haga algo aburrido hasta que sienta sueño. Evite la luz brillante durante ese tiempo.

NO DUERMA LA SIESTA
Esto hará que sienta más cansancio a la hora de dormir. Si necesita tomar una siesta hágalo antes de las 3pm y por menos de una hora.

ACUÉSTESE A SU HORA
Levántese y acuéstese a la misma hora todos los días, aun en fin de semana. Es más fácil conciliar el sueño cuando se tiene un ciclo de sueño regular.

PLANEE SU EJERCICIO
Hacer ejercicio regularmente puede mejorar su patrón de sueño, pero no lo haga demasiado cercano a la hora de dormir (por lo menos 4 horas antes).

CREE RITUALES DE SUEÑO
Es importante darle al cuerpo señales de que es hora de dormir, como escuchar música relajante, tomar té de hierbas o meditar.

USE LA CAMA SÓLO PARA DORMIR
Evite usar la cama para ver televisión, pagar las cuentas, trabajar o leer.

EVITE LA CAFEÍNA, LA NICOTINA Y EL ALCOHOL
La cafeína y la nicotina son estimulantes y el alcohol puede causar sueño pobre y fragmentado. Evítelos por lo menos 4 horas antes del irse a dormir.

COMA ALGO LIGERO ANTES DE IRSE A DORMIR
Dormir con el estómago muy lleno o muy vacío puede interferir con el sueño.

DÉSE UN BAÑO CALIENTE
Un baño caliente por 90 minutos antes de irse a dormir levanta la temperatura del cuerpo, pero luego al bajar la temperatura produce sueño.

REFRESQUE SU HABITACIÓN
Dormirse en un ambiente caldeado puede ser difícil. Se recomienda mantener la habitación a 65 grados, con suficientes mantas para permanecer abrigado.

MANTENGA OSCURIDAD Y EVITE LOS RUIDOS
Tener cortinas que impidan que penetre la luz o usar un antifaz puede ayudar a bloquear la luz y usar tapones para los oídos o una máquina que produce ruido blanco puede evitar los ruidos.

REAJUSTE SU RELOJ BIOLÓGICO
Tan pronto como se levante por la mañana salga de la casa y póngase de cara al sol por 15 minutos.

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MÁS SOBRE LA MELATONINA

La melatonina le “abre las puertas” al sueño, o sea que el tiempo es muy importante para conseguir el efecto deseado. [14]

EN GENERAL: Debe evitarse exponerse a luz brillante después que haya oscurecido por la noche ya que interrumpe el ritmo de la melatonina y altera el ritmo diario (circadian) de su reloj interior. Cuando se la usa para promover un sueño ininterrumpido por la noche, es mejor tomar la melatonina 30 minutos antes de la hora en que desea quedarse dormido.

CUANDO SE LA TOMA A LAS 8PM: La melatonina avanza el reloj interior, y hace que creamos que es más tarde de lo que es. La dosis para dormir es de 1 a 5 mg.

CUANDO SE LA TOMA AL AMANECER: La melatonina retrasa al reloj interior y nos hace sentir que es más temprano de lo que es. La dosis al amanecer es de 1 mg.

TOMAR MELATONINA CUANDO SE VIAJA AL ESTE: Si va a viajar de San Francisco a París tome la melatonina al amanecer hora de San Francisco (que puede ocurrir cuando ya está en el avión). Luego, una vez que haya llegado, tome la melatonina al amanecer en la hora de París. Durante uno o dos días antes de regresar tome la melatonina al amanecer, hora de París, y al amanecer, hora de San Francisco.

TOMAR MELATONINA CUANDO SE VIAJA AL OESTE: Si va a viajar de San Francisco a Beijing, una vez que llegue tome la melatonina al amanecer, hora de Beijing. Antes de regresar, tome melatonina al amanecer, hora de Beijing, y luego, una vez que ha regresado al amanecer, hora de San Francisco. Nota: Parece que el viajar hacia el oeste causa menos “jet lag” y que la melatonina no es muy efectiva para los viajes hacia el oeste si no cruzan al menos 4 cambios de zona horaria.

MEDICAMENTOS Y SUSTANCIAS QUE PUEDEN INTERACTUAR NEGATIVAMENTE CON LA MELATONINA: Los anticoagulantes y las medicinas contra la formación de plaquetas, las medicinas antidiabetes, Benzodiacepinas, la cafeína, los depresivos CNS, las medicinas para la concepción, Flumacenil (Romazicon), Fluxoxamina (Luvox), los supresores del sistema inmunológico, Nifedipina GITS (Procardia XL), Verapamil (Calan, Covera, Isoptin, Verelan). [29]

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Referencias:

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2. Bryant PA, Trinder J, et al. “Sick and tired: Does sleep have a vital role in the immune system?” Nat Rev Immunol 4(6): 457-67 (2004)

3. Toh, L.A., Tolley, E.A. & Krueger, J.M. “Sleep as a prognostic indicator during infectious disease in rabbits.” Proc Soc Exp Biol Med 203: 179-192 (1993).

4. Dew MA et al. “Healthy older adults’ sleep predicts all-cause mortality at 4 to 19 years of follow-up.” Psychosom Med. 65: 63-73 (2003).

5. Everson CA. “Sustained sleep deprivation impairs host defense.” Am J Physiol. 265: R1148-R1154 (1993)

6. Rechtschaffen A, Gillliland MA, Bergmann BM, & Winter JB. “Physiological correlates of prolonged sleep deprivation in rats.” Science 221: 182-184 (1983).

7. Landis CA & Whitney JD. “Effects of 72 hours of sleep deprivation on wound healing in the rat.” Res. Nurs. Health 20: 259-267 (1997).

8. Loomis AL, Harvey EN, Hobart G. “Potential rhythms of the cerebral cortex during sleep.” Science 81: 597-98 (1935).

9. Aserinksy E, Kleitman N. Regularly occurring periods of eye motility and concomitant phenomena, during sleep. Science 118: 273-74 (1953).

10. Blask DE, Sauer LA & Dauchy RT. “Melatonin as a chronobiotic/anti-cancer agent: cellular, biochemical and molecular mechanisms of action and their implications for circadian-based cancer therapy.” Current topics in Medicinal Chemisty 2: 113-132 (2002).

11. Lerner AB, Case JD, Takahashi Y et al. “Isolation of melatonin, the pineal gland factor that lightens melanocytes.” Journal of the American Chemical Society 80: 2587 (1958).

12. Lerner AB, Case JD, & Heinzelmann RV. “Structure of melatonin. Journal of the American Chemical Society.” 81: 6084-6085 (1959).

13. Malpaux B, Migaud M, Tricoire H, & Chemineau P. “Biology of mammalian photoperiodism and the critical role of the pineal gland and melatonin.” Journal of Biological Rhythms 16: 336-347 (2001).

14. Reiter RJ. “The melatonin rhythm: both a clock and a calendar.” Experientia 49: 654-664 (1993).

15. Guerrero JM & Reiter RJ. “Melatonin-immune system relationships.” Current Topics in Medicinal Chemistry 2: 167-180 (2002).

16. Tan DX, Manchester LC, & Hardeland R et al. “Melatonin: a hormone, a tissue factor, an autocoid, a paracoid and a antioxidant vitamin.” J of Pineal Research 34: 75-78 (2003).

17. Kennaway DJ & Wright H. “Melatonin and circadian rhythms.” Current Topics in Medicinal Chemistry 2: 199-209 (2002).

18. Sauer LA, Dauchy RT & Blask DE. “Polyunsaturated fatty acids, melatonin, and cancer progression.” Biochemical Pharmacology 61: 1455-1462 (2001).

19. Lissoni P. “Is there a role for melatonin in supportive care?” Supportive Cancer Care 10: 110-116 (2002).

20. Palmblad, J. et al. Stressor exposure and immunological response in man: interferon-producing capacity and phagocytosis. J. Psychosom. Res. 20: 193-199 (1976).

21. Horohov DW, Pourciau SS, Mistric L, Chapman A, & Ryan DH. “Increased dietary fat prevents sleep deprivation induced immune suppression in rats.” Comp Med 51: 230-233 (2001).

22. Linsen SM, Zitman FG, Breteler MHM. “Defining benzodiazepine dependence: the confusion persists.” Eur Psychiatry 10: 306-11 (1995).

23. Gudex C. “Adverse effects of benzodiazepines.” Soc Sci Med 33: 587-96 (1991).

24. Lader M. “Withdrawal reactions after stopping hypnotics in patients with insomnia.” CNS Drugs. 10: 425-40 (1998).

25. Morin CM, Colecchi C, Stone J, Sood R, & Brink D. “Behavioral and pharmacological therapies for late-life insomnia: a randomized controlled trial [comment].” JAMA 281: 991-9 (1999).

26. Lai HL & Good M. “Music improves sleep quality in older adults.” J Adv Nurs 49(3): 234-44 (2005).

27. Cohen L, Warneke C, et al. “Psychological adjustment and sleep quality in a randomized trial of the effects of a Tibetan yoga intervention in patients with lymphoma.” Cancer 100(10): 2253-60 (2004).

28. Hrushesky WJM, Blask D, Lissoni P. “Melatonin, Chronobiology, and Cancer.” Paper presented at: National Cancer Institute Invited Speaker Series; February 28, 2003; Bethesda, MD.

29. Natural Medicines Comprehensive Database. www.naturaldatabase.com

INTRODUCTION

Oxidative stress is a condition in animal cells where increased free radicals are produced, or when the cell doesn’t have enough antioxidants. Oxidative stress happens in inflammation and infection, and can lead to cellular degeneration. Oxidative stress also helps cause many types of cancer, including ovarian cancer. One of the most important cancer journals, the Journal of National Cancer Institute, said that ovarian cancer is caused by inflammation. (Ness and Cottreau 1999) It is also now known that ovarian cancer patients have increased levels of oxidative stress and decreased levels of antioxidants, such as vitamins C and E, in comparison to healthy controls. (Senthil, Aranganathan et al. 2004)

Chemotherapy drugs used in the treatment of ovarian cancer work, in part, by inducing even higher levels of oxidative stress to attack cancer cells. This increased oxidative stress also causes chemotherapy related side effects. Oncologists have been concerned that antioxidants, which can decrease oxidative stress, can therefore also decrease chemotherapy treatment effectiveness or increase resistance to chemotherapy.

Using antioxidants during chemotherapy is an important and controversial question among health care providers, patients, and their support teams and we have previously researched this subject thoroughly for prostate, breast, lung, and colon cancers. In this article, we turn our focus to ovarian cancer and have searched for published research that would support or discourage the use of antioxidants in combination with chemotherapy. The overwhelming majority of studies find a favorable interaction between antioxidants and chemotherapy because antioxidants can decrease chemotherapy side effects, increase treatment effectiveness, and decrease resistance to chemotherapy.

No substantial clinical research has emerged to support the assertion that antioxidants are contraindicated during chemotherapy. The research that supports the concern about the use of antioxidants during chemotherapy treatment does not directly combine antioxidants and chemotherapy in human, animal, or cell culture studies. Rather, the studies that support this view simply show that ovarian cancer cells that are resistant to chemotherapy often have naturally higher levels of glutathione, which is one of the body’s most important and natural antioxidants. (Zeller, Fruhauf et al. 1991; Kudoh, Kita et al. 1994; Chen, Hutter et al. 1995; Parekh and Simpkins 1996; Akcay, Dincer et al. 2005; Das, Bacsi et al. 2006) Glutathione can facilitate the detoxification and excretion of many chemotherapy agents. (Akcay, Dincer et al. 2005; Das, Bacsi et al. 2006) Buthionine sulfoximine is a chemical that lowers glutathione levels and numerous studies also find that adding buthionine sulfoximine sensitizes ovarian cancer cells to chemotherapy drugs. (Zeller, Fruhauf et al. 1991; Kudoh, Kita et al. 1994; Parekh and Simpkins 1996; Sharp, Smith et al. 1998; Lewandowicz, Britt et al. 2002) Beyond the references provided here, many other studies have also explored this topic with similar findings.

For this paper, we searched for clinical or laboratory data published in peer-reviewed medical journals, conducted by cancer researchers in universities and medical research facilities around the world. Some of these studies are still in early stages and include only laboratory or animal data while others have advanced to include human volunteers. We organized these data into the major categories of specific chemotherapy drugs. Within each section for a specific drug are found the research on combinations of that drug with various antioxidants, grouped by the name of the antioxidant in alphabetical order. We also point out specifically which studies were conducted in a laboratory (i.e. used cancer cell cultures), used animals, or involved human volunteers. As each antioxidant appears in the paper for the first time, we provide some introduction to the antioxidant including what food sources naturally contain it, other common applications in clinical use, and typical dosages. The dosages given are not necessarily appropriate for all patients and should be individualized with practitioner guidance.

5-Fluorouracil

LENTINAN

Lentinan is a polysaccharide derived from the edible Japanese shiitake mushroom (Lentinula edodes). It possesses immunostimulating antitumor properties.

» Shiitake mushroom extracts: Typical doses range from 100 to 400 mg per day.

A patient with recurrent ovarian cancer in the pelvis had a partial response to cisplatin and 5-fluorouracil. She then received an operation but the tumor could not be completely removed. Following the operation, cisplatin no longer produced any effect against the remaining tumor. She was then treated with lentinan (2 mg per week) and 5-fluorouracil. Four months after the start of this therapy, the tumor, which had become resistant to cisplatin, disappeared completely. At the time this case report was written in 1989, the patient had resumed normal activities and had been free of disease for six months, confirmed by physical exam, cytologic examination, CT, scintigraphy, and B scope. (Shimizu, Hasumi et al. 1989)

Cisplatin

ACETYL-L-CARNITINE

Acetyl-L-carnitine is an antioxidant that comes from dietary sources, such as dairy and meat. As a supplement, it is used for Alzheimer’s, age related memory loss, cognitive deficits, and neuropathies.

» Acetyl-L-carnitine: Typical doses range from 500 to 4000 mg. If using high doses, taking half the dose twice daily is beneficial.

In an animal study with rats, cisplatin or paclitaxel was combined with Acetyl-L-carnitine. Acetyl-L-carnitine significantly reduced toxicity to the nerves of both cisplatin and paclitaxel. In two different ovarian cancer cell lines, Acetyl-L-carnitine did not change the anti-tumor activity of cisplatin or paclitaxel. (Pisano, Pratesi et al. 2003)

CAFFEINE

Caffeine is one of the most consumed drugs in the world and sources include coffee, black tea, green tea, oolong tea, guarana, mate, and kola nut. Caffeine in combination with pain medication can be used in treating headaches.

» Caffeine: Typical doses range from 150 mg to 600 mg. Six ounces of drip coffee typically contains between 80 mg and 130 mg of caffeine. A double shot of espresso typically contains between 60 mg and 100 mg of caffeine.

Caffeine was found to significantly enhance cisplatin cytotoxicity in human ovarian cancer cells in two different laboratory studies. (Boike, Petru et al. 1990; Schiano, Sevin et al. 1991)

CURCUMIN

Curcumin is a polyphenol and is an extract of the Indian curry spice plant turmeric. Curcumin is known for its anti-tumor, antioxidant, anti-amyloid, and anti-inflammatory properties. It also promotes healthy bile excretion and healthy platelet function.

» Curcumin: The best supplements contain curcumin at 75% or higher concentration. Typical doses range from 500 mg to 2,000 mg daily. Take with meals, as curcumin can cause stomach upset when taken on an empty stomach. Bioavailability and potency are increased when combined with Bioperine, an extract from black pepper.

In two different ovarian cancer cell types, curcumin increased cisplatin effectiveness. Curcumin was effective when added at the same time as cisplatin, or 24 hours prior to cisplatin treatment. One of the ovarian cancer cell lines had a high level of IL-6 (a cytokine linked to cancer, poor prognosis, and cisplatin resistance). Curcumin inhibited the production of IL-6 in these cells. (Chan, Fong et al. 2003)

ETHYLENEDIAMINETETRAACETIC ACID (EDTA)

EDTA is a chelating agent that binds to metals and assists in their removal from the body.

» EDTA: The dose when used for lead poisoning is typically administered intravenously at 50 mg per kilogram of body weight to a maximum dose of 3 g diluted with 5% dextrose or 9% sodium chloride. Intravenously, EDTA commonly causes abdominal cramps, anorexia, nausea, vomiting, diarrhea, headache hypotension, exfoliative dermatitis, and a burning sensation and pain at the site of infusion. EDTA must be administered by a qualified health care practitioner.

When EDTA was combined with one of the chelatable elements, such as bismuth, calcium, cadmium, copper, iron, magnesium, selenium, vanadium, or zinc in cisplatin sensitive and resistant human ovarian cancer cells, together with the chemotherapy drug cisplatin, the treatment effect of cisplatin was enhanced as compared to cisplatin treatment alone. (Maier, Purser et al. 1997)

EGCG

Epigallocatechin-3-gallate (EGCG) is the principal polyphenol found in green tea.

» EGCG: One cup of green tea contains between 10 mg and 400 mg of polyphenols depending on the source, amount of leaves used, and steeping time. EGCG may be conveniently obtained from extracts. A good product contains 725 mg, standardized to 98% polyphenols, 45% of which is EGCG.

In ovarian cancer cells, EGCG increased cisplatin treatment effect. In three different types of ovarian cancer cells (SKOV3, CAOV3, and C200), EGCG increased the potency of cisplatin by three to six fold. (Chan, Soprano et al. 2006)

GENISTEIN

Genistein is an isoflavone found in legumes, especially soybeans. Isoflavones are antioxidants that counteract the damaging effects of free radicals in body tissues. Isoflavones, such as genistein, also have anti-angiogenic effects, blocking the formation of new blood vessels needed to support the growth of tumors.

» Genistein: A good product will use organic non-GMO genistein. To achieve anti-tumor effects, the target daily dose, based on animal studies and calculations for similar human dosage, is 1,500 mg. The recommended dose for further research is between 100 mg and 1,100 mg. (Boik 2001) One cup of soy milk will contain on average about 45 mg of genistein and the other related isoflavones.

When genistein and daidzein were used in combination with cisplatin and topotecan in five different ovarian cancer cell lines, the treatment effect was enhanced. In combination with paclitaxel, genistein and daidzein did not interfere with the treatment, but also did not increase the effect of the treatment. (Gercel-Taylor, Feitelson et al. 2004)

GINSENOSIDE RH2 FROM PANAX GINSENG

Ginsenosides are active ingredients derived from ginseng, one of the most widely known herbal medicines in the world and commonly used for its immune stimulating and anti-tumor properties. (Boik 2001)

» White American Ginseng Extract: Commonly used dosage levels

of ginseng extract range between 200 mg and 1,000 mg.

In three animal studies, ginsenoside administered together with cisplatin significantly inhibited ovarian tumor growth and prolonged survival beyond that of cisplatin treatment given alone. Ginsenoside did not cause any side effects. (Kikuchi, Sasa et al. 1991; Tode, Kikuchi et al. 1992; Nakata, Kikuchi et al. 1998) One of these studies found that oral (but not intraperitoneal) treatment with Rh2 resulted in apoptosis in tumor cells and an increase in natural killer activity in spleen cells. (Nakata, Kikuchi et al. 1998)

GINGER

Ginger, also known as sheng jiang or gan jiang in Chinese, is a spice and dietary ingredient that can also be obtained as a supplement. It is often used for motion sickness and nausea.

» Ginger: Typical dosage levels of ginger range between 2 g to 4 g daily.

In a randomized controlled crossover study, researchers at the Gynecologic Oncology Unit of Bangkok Medical College investigated whether a daily dose of 1,000 mg of ginger could reduce vomiting in women with ovarian cancer receiving cisplatin chemotherapy. At the first cycle of chemotherapy, women were randomized to either ginger or placebo, in addition to standard anti-nausea medication. For the second cycle, women then crossed over to the other group, so the group which first received ginger then received placebo, and the group first on placebo switched to ginger. There was no reduction in either nausea or vomiting with ginger treatment, however there was less restlessness. (Manusirivithaya, Sripramote et al. 2004)

GLUTATHIONE

Glutathione is one of the most powerful and important natural antioxidants produced in the body.

» Glutathione: Typical dosage ranges between 50 mg and 600 mg daily. N-acetyl cysteine is the pre-cursor of glutathione and is more efficiently absorbed. When taking glutathione or N-acetyl cysteine, combine with three times as much vitamin C to prevent these amino acids from being oxidized in the body and to ensure their ability to act as antioxidants.

In a double-blind, randomized trial from England, 151 patients with ovarian cancer (stages I to IV) were given either cisplatin alone (100 mg per m2) or cisplatin combined with intravenous glutathione (3 g per m2). The researchers’ goal was to see whether the addition of glutathione could help patients complete the planned six cycles of cisplatin chemotherapy. They found that 58% of patients receiving additional glutathione completed six cycles of treatment, while only 39% of patients receiving cisplatin alone were able to complete all six cycles. Patients in the glutathione plus cisplatin group also had significantly less depression, vomiting, neuropathy, hair loss, shortness of breath, difficulty concentrating, and kidney side effects. They were also better able to continue their ordinary daytime activities. (Smyth, Bowman et al. 1997)

In a randomized controlled trial from Italy, 31 patients with recurrent ovarian cancer who had been in remission for at least one year were given either cisplatin alone (50 mg per m2) or cisplatin and glutathione (2.5 g). Researchers found that 56% of patients in the glutathione group were able to complete the full dose of chemotherapy, compared to only 27% in the cisplatin only group. The glutathione plus cisplatin group also experienced lower levels of neuropathy, without decreasing the anti-tumor activity. (Colombo, Bini et al. 1995)

In a prospective, randomized study, 33 women with recurrent ovarian cancer were given cisplatin alone or cisplatin combined with glutathione. The patients experienced minimal neurotoxicity with no reduction in treatment effectiveness by the addition of glutathione to cisplatin therapy. (Bogliun, Marzorati et al. 1992)

MELATONIN

Melatonin is a hormone that is released from the pineal gland in the evening and promotes normal sleep; its secretion diminishes significantly with age. It is known to help maintain cell health and many people take it to improve sleep. It is also known to reduce metastasis in cancer patients. In most published studies, melatonin shows a beneficial effect, although it has been reported that in a small proportion of people, melatonin can paradoxically cause sleep disturbance. In others, there can be residual daytime drowsiness, which is usually resolved by using a lower dose.

» Melatonin: Typical dosages range from 1 mg to 20 mg. If aiming for a high dosage, one should start with 1 mg and increase the dosage slowly by 1 mg every 3 to 7 days. The ideal is to achieve peak blood levels of melatonin at about 2 am. To do so, one can take the melatonin at bedtime, ideally between 9 pm and 10 pm.

In cisplatin-sensitive and resistant ovarian cancer cells, melatonin enhanced cisplatin treatment effectiveness. (Futagami, Sato et al. 2001)

PROTEIN-BOUND POLYSACCHARIDE-K (PSK)

Polysaccharide-K (PSK) is extracted from a mushroom called turkey tail. Other names include Trametes versicolor and Coriolus versicolor (Latin), yun zhi (Chinese), and kawaratake (Japanese). It is commonly used to boost immune health and often used with cancer patients.

» PSK: Typical doses for cancer patients range between 2 g and 6 g.

In human ovarian cancer cells, PSK was found to enhance the treatment effect of cisplatin in a laboratory study. (Kobayashi, Kariya et al. 1994)

QUERCETIN

Quercetin is a flavonoid found in capers, apples, tea, onions, red grapes, citrus fruits, leafy green vegetables, cherries, and raspberries. Quercetin has anti-inflammatory activity, inhibits allergic and inflammatory reactions, and has strong antioxidant activity.

» Quercetin: Typical dosages range from 200 mg to 1,200 mg daily.

Quercetin increased the treatment effect of cisplatin in ovarian cancer cells. (Scambia, Ranelletti et al. 1990) In another laboratory study, when quercetin and genistein were combined, their anticancer effect was greater than either antioxidant used alone. (Shen and Weber 1997)

RESVERATROL

Resveratrol is an antioxidant derived from the red pigment of grape skins.

» Resveratrol: Typical doses range from 25 mg to 250 mg per day.

Resveratrol in combination with either cisplatin or doxorubicin increased the treatment effect in ovarian and uterine cancer cells. In addition, resveratrol protected rats from doxorubicininduced heart toxicity. (Rezk, Balulad et al. 2006)

RUTIN AND HESPERIDIN

The flavonoid rutin can be obtained from sources such as buckwheat, the buds of the Chinese herb Sophora japonica, and propolis. Hesperidin is a flavonoid found in citrus fruits, such as lemons and oranges.

» Rutin: Typical doses range from 500 mg to 1,000 mg daily.

» Hesperidin: Typical doses range from 10 mg to 100 mg.

Rutin and hesperidin had no effect on ovarian cancer cells, either alone or in combination with cisplatin. (Scambia, Ranelletti et al. 1990)

SELENIUM

Selenium is an essential trace mineral found in variable amounts in food depending on the soil content of selenium. Brazil nuts are the single best food source of selenium. One of its roles in the body is as an antioxidant and it is most widely known as a cancer preventive.

» Selenium (mineral): The US adult Tolerable Upper Intake Level (UL) is 400 micrograms a day and the Lowest Observed Adverse Effects Level (LOAEL) for adults is about 900 micrograms daily. There are several different forms of selenium. Se-Methylselenocysteine is a highly bioavailable form because it is not incorporated within a protein such as the form selenomethionine. We recommend getting selenium either in the organically bound forms, such as of Se-Methylselenocysteine, or a combination of selenium compounds with L-selenomethionine, sodium selenate, selenodiglutathione, and Se-methylselenocysteine.

Mice with ovarian tumors did not develop drug resistance to cisplatin treatment when they were also treated with selenite or selenomethionine. In contrast, when mice did not receive supplements, and only received cisplatin treatment, they quickly developed drug resistance. Selenite was found to enhance cisplatin treatment in ovarian tumors. Treatment with sulfite or methionine did not affect resistance to cisplatin. (Caffrey and Frenkel 2000; Frenkel and Caffrey 2001)

SILYBIN

Silybin (also called silibinin) is an important active compound found in silymarin, extracted from blessed milk thistle (Silybum marianum).

» Silymarin: Silibinin is the most biologically active constituent found in silymarin and isosilybin B complex is the most efficient constituent of silymarin in maintaining healthy cell division. Typical dosages range from 100 mg to 900 mg daily. An example of a good product is one containing 900 mg, standardized to 80% silymarin (720 mg), 30% silibinin (270 mg), and 4.5% isosilybin B complex (40.5 mg).

When silybin was used together with cisplatin in human ovarian cancer cells, there was a statistically significant increase in treatment effectiveness. In mice with ovarian cancer, tumor weight inhibition increased from 80% in mice treated with cisplatin alone to 90% in mice treated with a combination of silybin and cisplatin. Mice receiving a combination of silybin and cisplatin also recovered earlier in regards to weight loss compared to mice treated with cisplatin alone. Antiangiogenic (reduction in blood supply to the tumor) effect of silybin was also demonstrated. (Giacomelli, Gallo et al. 2002) In a second study, silybin was found to increase the effect of cisplatin in ovarian cancer cells resistant to cisplatin. (Scambia, De Vincenzo et al. 1996)

VITAMIN B3

Niacin (nicotinic acid) and niacinamide (nicotinamide) are two forms of vitamin B3. Dietary sources include poultry, fish, eggs, peanuts, brewers yeast, rice bran, wheat bran, legumes, mushrooms, and nuts.

» Vitamin B3: Typical doses can range between 100 mg and 1200 mg per day. Slow dose escalation is essential to acclimate the body to the “niacin flush.” Some people find that the niacinamide version does not cause flush.

In a laboratory study using cisplatin-resistant rat ovarian tumor cells, vitamin B3 significantly enhanced the treatment effect of cisplatin. However, this same treatment had no substantial effect on the cisplatin-sensitive rat ovarian tumor cells. In the live animal part of the same study, cisplatin given alone had no antitumor activity in the resistant tumor. When vitamin B3 was added, the survival time increased almost 50% in the group receiving both cisplatin and vitamin B3. (Chen and Zeller 1993)

VITAMIN E

Vitamin E includes several related compounds: Tocopherols and tocotrienols, each of which have four subtypes of alpha, beta, gamma, and delta. Previously, only alpha-tocopherol was considered important, however each type has unique contributions to health. The best dietary sources of vitamin E are considered to be unrefined, cold-pressed vegetable oils (such as wheat germ, sunflower seed, and olive oils) and raw or sprouted seeds, nuts, and grains.

» Vitamin E: Avoid synthetic vitamin E, such as alpha-tocopherol or succinate. Seek out the mixed tocopherols, including tocopherols and tocotrienols. Typical dosage ranges from 50 IU to 800 IU daily.

Researchers from Italy’s National Cancer Institute conducted a study in which they randomized 47 patients to receive either vitamin E (alpha-tocopherol, 300 mg per day) during cisplatin chemotherapy or cisplatin alone. Vitamin E was given orally before cisplatin chemotherapy and continued for three months after completion of treatment. Twenty-seven patients completed six cycles of cisplatin chemotherapy. The vitamin E plus cisplatin group had significantly less neurotoxicity compared to the chemotherapy alone group. Severity of neurotoxicity was also significantly lower. Addition of vitamin E also did not reduce anti-tumor effectiveness of cisplatin or longevity. (Pace, Savarese et al. 2003)

Carboplatin and Cisplatin

GLUTATHIONE

Researchers at the National Institute for the Study and Cure of Cancer in Milan, Italy published a study in which they tested whether glutathione can reduce side effects and increase effectiveness of high-dose carboplatin and cisplatin chemotherapy. In this study, fifty consecutive eligible patients with previously untreated stage III or IV ovarian cancer received two cycles of cisplatin and carboplatin chemotherapy, followed by surgery, and again two cycles of chemotherapy. Patients received glutathione (2,500 mg) before each cisplatin or carboplatin treatment. The toxicity was moderate with lack of significant kidney toxicity. In this group of patients, median survival was 48 months, better than would have been expected if treating with chemotherapy alone. (Bohm, Oriana et al. 1999)

Cisplatin and Paclitaxel

VITAMIN E

Peripheral neuropathy, or damage to the nerves in the hands and feet, can be a painful and sometimes long-lasting side effect of chemotherapy treatment, making walking and handling objects with the hands more difficult. Paclitaxel and the family of platinum chemotherapy drugs are the most likely to cause this often debilitating problem. In a randomized controlled trial, researchers at the University of Patras Medical Center in Greece tested the ability of vitamin E at a daily dose of 600 mg (900 IU) to prevent neuropathy caused by six courses of cisplatin and/or paclitaxel. The sixteen patients in the treatment group received vitamin E during chemotherapy and continuing for three months after that treatment ended, while the fifteen patients in the control group received no vitamin E. The risk of developing peripheral neuropathy was reduced by 66% in the group receiving vitamin E. It is important to add that the research team also did a pre-clinical animal study, which showed that in mice, vitamin E did not interfere with the ability of cisplatin to suppress tumor growth or increase life span. (Argyriou, Chroni et al. 2005)

Cyclophosphamide

GINSENOSIDE RG 3

In an animal study using mice with ovarian cancer, ginsenoside Rg3 was used in combination with cyclophosphamide. Mice treated with this combination lived longer and tumor inhibition was higher than mice receiving chemotherapy alone. The combination of ginsenoside Rg3 and cyclophosphamide decreased blood supply to the tumor more than cyclophosphamide alone. Mice receiving ginsenoside Rg3 alone had even greater decrease in blood supply to the tumor than mice receiving chemotherapy alone or a combination of chemotherapy and ginsenoside Rg3. (Xu, Xin et al. 2007)

Cisplatin and Cyclophosphamide

SELENIUM, VITAMIN E, VITAMIN C, BETA-CAROTENE, RIBOFLAVIN, AND NIACIN

In a pilot clinical study, the dietary supplement Protecton Zellactiv (Smith Kline Beecham, Germany), which contains selenium (200 mcg daily), vitamin E, beta-carotene, riboflavin, niacin, and vitamin C was used together with chemotherapy. Researchers from Pomeranian Academy of Medicine in Poland investigated whether the Protecton Zellactiv could influence oxidative stress, glutathione levels, or reduce side effects in women with ovarian cancer receiving cisplatin and cyclophosphamide chemotherapy. Women using this dietary supplement experienced significantly less nausea, vomiting, diarrhea, mouth sores, hair loss, flatulence, abdominal pain, weakness, malaise, or loss of appetite. Researchers also found an increase in glutathione peroxidase, which may have helped protect those women against chemotherapy toxicity. (Sieja and Talerczyk 2004)

GLUTATHIONE

In a phase II study from Italy, researchers gave 20 women with stage III or IV ovarian cancer a combination of cisplatin (45 mg per m2), cyclophosphamide (900 mg per m2), and intravenous glutathione (2,500 mg). Of these women, 55% achieved a complete response. Median survival was 26.5 months. At 35 month followup, five patients were still alive. There was little toxicity in general, and no kidney toxicity. (Locatelli, D’Antona et al. 1993)

In a clinical study from Italy, 79 women with stage III or IV ovarian cancer were treated with up to five courses of high-dose cisplatin (40 mg per m2 daily in normal saline, for four days) plus glutathione (2,500 mg as a short-term infusion before cisplatin), together with cyclophosphamide (600 mg per m2 as an i.v. bolus on day four). Of these women, 57% achieved a complete response and 25% achieved a partial response. These benefits were seen with only minimal toxicity, with severe neuropathy side effects occurring in only 4% of these women. (Di Re, Bohm et al. 1993)

In study of high-dose cisplatin (160 mg per m2) and cyclophosphamide (600 mg per m2) plus glutathione, 32 women with ovarian cancer were examined for neurotoxicity. After five courses of chemotherapy, no cases of disabling neuropathy were observed. (Pirovano, Balzarini et al. 1992)

In a pilot study, twelve patients with localized or stage III ovarian cancer were treated with cisplatin (90 mg per m2, i.v. in 250 ml of normal saline over 30 minutes), cyclophosphamide (600 mg per m2 i.v.) every 3 weeks, and glutathione (5 g in 200 ml of normal saline) prior to cisplatin. No cases of kidney toxicity or neurotoxicity were seen. Nine of 11 evaluable patients with stage III ovarian cancer achieved complete remission. (Bohm, Battista Spatti et al. 1991)

Forty consecutive patients with stage III and IV ovarian carcinoma were treated with cisplatin (40 mg per m2 daily for four consecutive days), cyclophosphamide (600 mg per m2 on day four) and glutathione (1,500 mg per m2, which is roughly equivalent to 37.5 mg per kg, based on a conversion using median height of 175 cm and median weight of 80 kg). Glutathione was administered over 15 minutes before each cisplatin treatment. This treatment was given every three to four weeks for five courses providing no severe toxicity or progression occurred. Surgery was performed on 18 patients prior to chemotherapy. After two to three courses of chemotherapy, 16 other patients received surgery. Surgery could not be carried out in six patients. Three patients were not evaluable for response because they discontinued treatment. Twenty-three patients (62%) achieved complete clinical remission. The overall (complete plus partial) response rate was 86%. Two patients achieved disease free status after a second surgery. Patients experienced some nausea and vomiting. Myelosuppression (a condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets) was acceptable. There was no renal impairment (likely because of the protective effect from glutathione). Neurotoxicity was the most significant cumulative toxicity, however it was not associated with motor dysfunction. It occurred in 24 out of 32 patients who received four to five courses. (Di Re, Bohm et al. 1990)

In a non-randomized study, 15 consecutive patients with ovarian cancer were treated with cisplatin and cyclophosphamide or the same regimen in combination with reduced glutathione (1,500 mg per m2, which is roughly equivalent to 37.5 mg per kg, based on a conversion using median height of 175 cm and median weight of 80 kg). Glutathione was administered prior to each chemotherapy treatment to seven patients. The efficacy of chemotherapy treatment was equal in both groups and therefore it was not reduced by glutathione pretreatment. Severity of myelosupression was reduced with glutathione. Two patients who received chemotherapy alone developed transient nephrotoxicity (toxicity to the nerves) while no patients receiving glutathione developed nephrotoxicity. (Oriana, Bohm et al. 1987)

Cisplatin and Hexamethylmelamine

VITAMIN B6 (PYRIDOXINE)

Vitamin B6 comes from a variety of dietary sources, such as turkey, tuna, spinach, banana, lentils, and potatoes.

» Vitamin B6: Typical doses range between 10 mg and 200 mg per day. Individuals using more than 100 mg per day for more than two months should be supervised by a health care professional as chronic overdose may lead to sensory neuropathy.

A randomized clinical trial included 248 patients with stage III to IV ovarian epithelial cancer. Of these, 114 patients had prior chemotherapy and 134 did not. They were randomized to one of four cisplatin and hexamethylmelamine regimens. Hexamethylmelamine was given at 200 mg per m2 orally on days 8 to 21 of each 21 day cycle. Cisplatin was given at two doses of 37.5 mg per m2 or 75 mg per m2. Half of the patients were randomized to also receive vitamin B6 at a dose of 300 mg per m2 (which is roughly equivalent to 7.5 mg per kg, based on a conversion using median height of 175 cm and median weight of 80 kg) orally on days 1 to 21. The overall response rate was 54% and 25% achieved a complete response. Patients receiving the higher dose of cisplatin had a greater response rate of 61%, while patients receiving lower doses had a response rate of 47%. The median response duration was 8.3 months. Response duration was shortened in the vitamin B6 group of patients and thus had an unfavorable effect on treatment effectiveness. Patients treated with higher dose cisplatin had more nausea and vomiting as well as increased neurotoxicity. Vitamin B6 significantly reduced neurotoxicity.

Doxorubicin

7-MONOHYDROXYETHLRUTOSIDE (MONOHER)

Flavonoids are beneficial antioxidants found in fruits and vegetables, especially red grape juice, green tea, soy, and many other legumes. One potential useful example of a beneficial flavonoid is monoHER, one of the most powerfully active antioxidants in flavonoid products, such as Venoruton, which is used to treat varicose veins. (van Acker and Boven, 1997) MonoHER is a derivative of the flavonoid rutin, obtained from many sources, such as buckwheat and the buds of the Chinese herb Saphora japonica. It is also found in propolis.

» Rutin: Typical dosages range from 500 mg to 1,000 mg daily.

The flavonoid monohydroxyethylrutoside (monoHER) prevented heart cell damage from doxorubicin by 15 fold. However, monoHER may also protect ovarian cancer cells from being effectively treated by doxorubicin. Specifically, monoHER reduced doxorubicin effectiveness in one type of ovarian cancer cell culture (A2780) and did not interfere with doxorubicin treatment in another ovarian cancer cell line (OVCAR-3). In practical terms, this means that monoHER used at high concentrations as demonstrated in this study has the potential to decrease the effectiveness of doxorubicin treatment. The authors of this study note that lower concentrations of monoHER, which are more realistic in clinical use, do not influenced the antitumor activity of doxorubicin. (Bruynzeel, Abou El Hassan et al. 2007)

In a combined laboratory and animal study, monoHER protected mice against doxorubicin-induced cardiotoxicity. Furthermore, monoHER did not interfere with the treatment effect of doxorubicin in human ovarian cancer cells or in mice with ovarian cancer. (van Acker, Boven et al. 1997)

TOPICAL 99% DIMETHYL SULFOXIDE (DMSO)

Dimethyl sulfoxide (DMSO) is a natural substance derived from wood pulp.

» Dimethyl sulfoxide (DMSO): This product is used topically in small amounts such as 1/8 teaspoon. Thorough cleaning of the skin prior to use is essential. Drying of the skin can occur. This should be a practitioner-guided approach.

Two patients with recurrent ovarian cancer receiving pegylated liposomal doxorubicin chemotherapy at the University of Arizona developed the painfully debilitating side effect called hand-foot syndrome, at the severe intensity level of grade 3. Their symptoms resolved over a period of one to three weeks while receiving topical 99% DMSO four times daily for 14 days. (Lopez, Wallace et al. 1999)

SPIRULINA

Spirulina is blue green algae that grows in tropical and subtropical alkaline waters with high-salt content. It is a rich source of dietary protein, B-vitamins, and iron.

» Spirulina: Typical doses range from 250 mg to 5 grams per day.

Spirulina did not interfere with the treatment effect of cisplatin in ovarian cancer cells. Additionally, spirulina protected rats from cisplatin-induced toxicity to the kidneys. The spirulina was given four days prior to chemotherapy treatment, on the day of chemotherapy, and four days after. (Mohan, Khan et al. 2006)

When mice were treated with spirulina (orally) along with doxorubicin, they were significantly protected from doxorubicininduced damage to the heart. They also had lower mortality: only 26% compared to 53% in mice treated with doxorubicin alone. In the laboratory portion of the study, spirulina did not reduce the anti-tumor activity of doxorubicin in ovarian cancer cells. (Khan, Shobha et al. 2005)

THEANINE

Theanine is an amino acid that is used for its anti-anxiety calming effects. Dietary sources include green tea as well as the edible Bay Bolete mushroom (Boletus badius).

» Theanine: Typical doses range from 50 mg to 200 mg per day.

In an animal study, mice with ovarian cancer were treated with either adriamycin alone or with adriamycin in combination with theanine. Adriamycin alone did not inhibit tumor growth. In contrast, when the same dose of adriamycin was used with theanine, tumor weight was reduced to 62% of the control level. When combined with theanine, the concentration of adriamycin in the tumor increased by 2.7 fold, however adriamycin concentrations in normal tissue decreased. (Sugiyama and Sadzuka 1998)

In a second animal study with mice with ovarian sarcoma, theanine was used in combination with doxorubicin. The combination enhanced reduction of metastasis to the liver. In the laboratory portion of the study, theanine increased the concentration of doxorubicin in ovarian cancer cells. (Sugiyama and Sadzuka 1999)

VITAMIN E

In 2004, a group of clinicians at New York’s Memorial Sloan-Kettering Cancer Center reported on the case of a women with ovarian cancer receiving the new chemotherapy drug pegylated liposomal doxorubicin in combination with vitamin E. This patient was experiencing significant vaginal irritation and burning, which began several days after her first round of chemotherapy. She was advised to avoid intercourse for three to five days after chemotherapy and to use both intravaginal vitamin E suppositories three times per week and vaginal estrogen tablets (initial course of 14 days followed by twice weekly usage), use of lubricants (Astroglide) during intercourse, and counseling. This combination approach allowed her to resume intercourse throughout the rest of her chemotherapy treatment. (Krychman, Carter et al. 2004)

Docetaxel

CURCUMIN

In mice with ovarian cancer, the combination of curcumin and docetaxel was more effective than docetaxel alone. Tumor mass was reduced by 66% compared to docetaxel therapy alone . In mice with ovarian cancer (which had developed resistance to docetaxel), treatment with docetaxel did not reduce tumor growth. Treatment with a combination of docetaxel and curcumin resulted in 58% tumor reduction. Docetaxel alone did not reduce angiogenesis, but when combined with curcumin, angiogenesis was reduced. Interestingly, curcumin alone had the strongest effect in reducing angiogenesis. This study found that one of the mechanisms by which curcumin controls cancer cell growth is by inhibition of NF-kappaB. (Lin, Kunnumakkara et al. 2007) Activation of NF-kappaB, a protein complex, is not favorable in cancer treatment as it leads to cellular events that promote inflammation, cell proliferation, angiogenesis, metastasis, and discourages cell death. NF-kappaB is associated with cancer risk, poor prognosis, and contributes to chemotherapy resistance. (Lee, Jeon et al. 2007; Sethi, Sung et al. 2008)

Irinotecan and Topotecan

GENISTEIN

In a cell culture study, genistein was used in combination with either irinotecan or topotecan. Genistein enhanced the treatment effect of these two chemotherapy drugs in ovarian as well as cervical cancer cells. (Papazisis, Kalemi et al. 2006)

Melphalan

SELENITE

In an animal study using mice with ovarian tumors, intraperitoneal injection of selenite (another form of selenium) prevented the development of resistance to melphalan as well as cisplatin. Selenite injection prevented increase in cellular glutathione. The method of selenite administration was important. When administered in drinking water or injected subcutaneously, selenite had little effect on the development of resistance. (Caffrey, Zhu et al. 1998) In a laboratory study by the same authors, Selenite was found to completely prevent ovarian cancer cell resistance to melphalan. (Caffrey, Zhu et al. 1998)

Forty patients with ovarian cancer had significantly lower selenium levels than matched control subjects. Higher stage of disease was associated with lower selenium levels. Patients with progressive disease had lower selenium levels than patients in remission. (Sundstrom, Yrjanheikki et al. 1984)

COMBINATIONS TO AVOID :

GLUTAMINE, LEUCINE, METHIONINE, AND TYROSINE

In human ovarian cancer cells, the amino acids glutamine, tyrosine, methionine, and leucine significantly reduced uptake of melphalan thereby decreasing effectiveness of treatment. (Vistica, Von Hoff et al. 1981; Dufour, Panasci et al. 1985)

Paclitaxel

COMBINATIONS TO AVOID: N-ACETYLCYSTEINE

In ovarian cancer cells, the antioxidant N-acetylcysteine decreased paclitaxel-induced cell death. (Goto, Takano et al. 2008)

Paclitaxel and Carboplatin

VITAMIN C, VITAMIN E, AND COENZYME Q10

Vitamin C, also called ascorbic acid, is a nutrient that humans cannot synthesize and must obtain from food. Almost all fresh vegetables and fruits are sources of vitamin C. Broccoli, cauliflower, citrus fruits, and tomatoes are examples of food sources particularly high in vitamin C.

» Vitamin C: Typical doses range from 60 mg to 1000 mg a day or up to bowel tolerance.

Coenzyme Q10 (CoQ10) is naturally synthesized in the body and is also available from food sources such as meat, poultry, fish, nuts, vegetables, fruits, and dairy. The amount of CoQ10 obtained from food is quite small compared to taking a supplement. The average intake of CoQ10 from food is less than 10 mg per day.

» Coenzyme Q10: Oil softgels have higher absorption. Typical daily doses of CoQ10 range from 30 mg to 300 mg and is best taken with food. About three weeks of daily dosing are necessary to reach maximal serum concentrations of CoQ10. Bioavailability is increased when combined with piperine. The most advanced version of CoQ10 is the more highly absorbable version called Ubiquinol.

Researchers in the Department of Obstetrics and Gynecology at University of Kansas Medical Center published a remarkable case report of two women with stage III-C ovarian cancer being treated with carboplatin and paclitaxel. The first woman began high-dose antioxidant therapy during her first round of chemotherapy, consisting of vitamin C, vitamin E, beta-carotene, CoQ10, a multivitamin/mineral complex, and intravenous vitamin C at a total dose of 60 g given twice weekly at the end of her carboplatin chemotherapy and prior to paclitaxel. Her CA-125 levels normalized after her first cycle of chemotherapy and remained normal at the time of publication, three and a half years after diagnosis. She also had no evidence of disease on CT scans of her abdomen and pelvis.

The second woman added antioxidants just prior to beginning chemotherapy, including vitamin C, beta-carotene, vitamin E, coenzyme Q10, and a multivitamin/mineral complex. At the completion of her six cycles of paclitaxel/carboplatinum chemotherapy, even though scans showed she still had remaining tumors, she refused further chemotherapy. She switched to intravenous ascorbic acid at 60 g twice weekly. Three years after diagnosis, she has normal CA-125 and no evidence of recurrent disease on physical exam. (Drisko, Chapman et al. 2003) Based on the successful treatment with these two patients, this team at the University of Kansas has initiated a non-randomized trial in which vitamin C is being combined with chemotherapy. For information, contact Jeanne Drisko, MD, at (913) 588-6104.

VITAMIN E AND VITAMIN A

Vitamin A (retinol) is a fat-soluble, antioxidant vitamin important for bone growth and vision. Vitamin A is ingested in a precursor form from animal foods and is especially plentiful in cod liver oil. Other good sources include butter and egg yolks as well as whole milk, cream, and yogurt.

» Vitamin A: Typical dosages range from 2500 IU to 25,000 IU.

The natural levels of antioxidants in the body in 28 ovarian and breast cancer patients were measured in a study to determine if decreased antioxidants correlate with toxicity from paclitaxel and carboplatin chemotherapy. The antioxidants that were measured were vitamin E (alpha-tocopherol) and vitamin A (retinol). Note that these antioxidants were not given as supplements, rather the natural level of these antioxidants was measured before and after chemotherapy and the amount varied among patients. There was a significant increase in vitamin E and vitamin A during chemotherapy treatment. Patients who experienced significant side effects from chemotherapy had low levels of vitamins A and E. Patients who had significantly higher levels of these vitamins during chemotherapy did not experience serious toxicity. (Melichar, Kalabova et al. 2007)

Antioxidants Used Alone

QUECETIN

In a phase I clinical trial of the flavonoid quercetin, researchers from Birmingham, UK gave quercetin by intravenous infusion at escalating doses at three week intervals, starting at 60 mg per m2 and increasing to 1,700 mg per m2 (which is roughly equivalent to 1.5 and 42 mg per kg respectively, based on a conversion using median height of 175 cm and median weight of 80 kg). At the highest dose, dose-limiting kidney toxicity occurred but there was no suppression of blood-cell production in the bone marrow. Overall, two of ten patients had kidney toxicity at the highest dose. The dose with the optimum ratio of effectiveness and safety was 945 mg per m2 (23.6 mg per kg) (eight at three week intervals and six at weekly intervals). From among these patients, one was a woman with ovarian cancer resistant to cisplatin. Following two courses of quercetin (420 mg per m2 or 10.5 mg per kg), the CA 125 had fallen from 295 to 55 units per ml. The researchers concluded that quercetin can be safely administered by intravenous bolus. They also saw inhibition of lymphocyte tyrosine kinase activity and evidence of antitumor activity. (Ferry, Smith et al. 1996)

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In most cases, colon cancer treatment involves chemotherapy. However, toxicity and tumor cell drug resistance are notable drawbacks to this treatment.

Although not commonly addressed in clinical consultation, scientific evidence suggests that combining certain chemotherapy treatments with specific antioxidants at defined dosages can improve drug effectiveness or may reduce side effect severity.

This issue is important because it has long been the opinion of most practicing oncologists that antioxidants should not be used concurrently with chemotherapy as it was believed that the combination might inhibit chemotherapy effectiveness. This reluctance stems, in part, from the fact that some chemotherapy drugs work by strongly promoting oxidation. This is especially the case for the class of chemotherapy drugs called anthracyclines (Adriamycin and epirubicin), the alkylating agents (chlorambucil, cyclophosphamide, thiotepa, and busulfan), and the platinum drugs (cisplatin and carboplatin). Antioxidants, by definition, inhibit oxidation, so it was believed that antioxidants would prevent these chemotherapy drugs from working properly.

The controversy around using antioxidants together with chemotherapy is not based on many studies that show an adverse effect of adding antioxidants to chemotherapy. Rather this controversy is based on several studies that show how depleting glutathione, which is a natural antioxidant in the body, can enhance the treatment effect of chemotherapy. (Meijer, Mulder et al. 1990; Mans, Schuurhuis et al. 1992; Doyle, Ross et al. 1995; Versantvoort, Broxterman et al. 1995; Zaman, Lankelma et al. 1995; Kurokawa, Nishio et al. 1997; Lee, Park et al. 2004) Although this has led many oncologists to believe that this means all antioxidants should not be combined with chemotherapy, there are numerous laboratory and human studies showing how combining chemotherapy with antioxidants can indeed be helpful.

In this systematic review, we searched for every paper on the combination of antioxidants and chemotherapy in colon cancer and found only one laboratory (and no human) studies demonstrating a harmful effect, which was the combination of the antioxidant N-acetyl cysteine with paclitaxel. (Alexandre, Nicco et al. 2006)

Chemotherapy drugs that cause high levels of “oxidative stress” are thought to rely in part on oxidative stress to kill cancer cells, but other effects of that oxidative stress may also be getting in the way of the effectiveness of the chemotherapy. This is because oxidative stress slows cell replication. However, chemotherapy relies on fast cancer cell replication to be effective because it is during the moment of cell replication that chemotherapy kills cancer cells. (Conklin 2000) One approach to addressing this problem is the addition of certain antioxidants at specific dosages to lessen oxidative stress, thus making the chemotherapy treatment more effective (Perumal, Shanthi et al. 2005).

The interaction between chemotherapy and antioxidants is more complex than simply promoting and inhibiting oxidative stress. There are several mechanisms by which chemotherapy drugs function and antioxidants also have a number of different effects on the body. Each antioxidant has a different interaction with chemotherapy and this effect can change based upon the dosage used. Because the chemotherapy-antioxidant debate often focuses almost exclusively on oxidative stress, in this paper we broaden that discussion to include the many mechanisms by which antioxidants help in the fight against colon cancer.

The question is really not whether antioxidants should be used in combination with chemotherapy but rather which should be used and at what dosages.

PURPOSE OF THIS PAPER
In this evidence-based review article, we discuss the results of current research showing how antioxidants may enhance or, in some cases, inhibit the therapeutic action of specific chemotherapy drugs used in the treatment of colon cancer. Some of these antioxidants may also reduce chemotherapy side effects or inhibit chemotherapy resistance in colon cancer cells. Finally, some of these antioxidants have been found to be useful for restoring the natural antioxidants in the body, which are often depleted after the completion of chemotherapy.

HOW NUTRIENT DEPLETION FROM CHEMOTHERAPY CAN OCCUR
Chemotherapy can cause nutrient depletion from two major side effects. One is nausea and vomiting, making it more difficult for the patient to maintain adequate nutrient intake. Another is toxicity to cells in the gastrointestinal tract, making it more difficult for the intestines to adequately absorb nutrients. Antioxidants are not the only nutrients to become depleted; vitamins, minerals, amino acids, and fatty acids may also be compromised, especially in patients who have suffered these side effects for a prolonged amount of time.

METHODS
We searched for clinical or laboratory data published in peer-reviewed medical journals, conducted by cancer researchers in universities and medical research facilities around the world. Some of these studies are still in early stages and include only laboratory or animal data while others have advanced to include human volunteers.

We organized these data into the major categories of specific chemotherapy drugs. Within each section for a specific drug are found the research on combinations of that drug with various antioxidants, grouped by the name of the antioxidant in alphabetical order. We also point out specifically which studies were conducted in a laboratory (i.e. using cancer cell cultures), which were conducted using animals, and which were conducted with human volunteers. As each antioxidant appears in the paper for the first time, we provide some introduction to the antioxidant including what food sources naturally contain it, other common applications in clinical use, and typical dosages. The dosages given are not necessarily appropriate for all patients and should be individualized with practitioner guidance.

MECHANISMS OF ANTIOXIDANTS IN CANCER THERAPY
There are various mechanisms by which antioxidants play a roll in cancer therapy.

AMP-activated protein kinase (AMPK)
AMPK is an enzyme that helps inhibit the growth of some cancers (including colon cancer) when it is activated. AMPK can be activated by exercise and fasting, and by genes that suppress tumors. (Shaw, Kosmatka et al. 2004; Luo, Saha et al. 2005)

Antioxidants that are known to activate AMPK and suppress growth of colon cancer include genistein (Hwang, Ha et al. 2005), green tea or the compound found in green tea called EGCG, (Hwang, Ha et al. 2007) selenium, (Hwang, Kim et al. 2006) and capsaicin, which is found in chili peppers. (Kim, Hwang et al. 2007)

BCL-2 Family
The proteins in the BCL-2 family can determine whether a cell lives or dies. The following are proteins in this family:
1) BCL-2 and BCL-XL are proteins that promote cell survival.
2) BH3-only proteins can sense stress in a cell and can send a signal for the cell to die.
3) Bax and Bak are proteins that, when activated, lead to cell death. In the development of colon cancer, there are frequently mutations in the genes encoding for Bax. (Rupnarain, Dlamini et al. 2004; Woerner, Kloor et al. 2005; Fernandez-Luna 2007; Adams and Cory 2007)

The antioxidant genistein activates Bax. (Hwang, Ha et al. 2005) While the antioxidants N-acetyl cysteine and vitamin E and the chemotherapy agent 5-fluorouracil do not activate Bax when used alone, when either antioxidant is combined with 5-fluorouracil, Bax expression doubles, meaning that the combination is superior to chemotherapy used alone. (Adeyemo, Imtiaz et al. 2001)

Caspase-3
Caspase-3 is an enzyme that promotes cell death. (Porter and Janicke 1999) The above-mentioned activation of Bax and Bak (from the BCL-2 family) precede activation of caspases such as caspase-3. (Fernandez-Luna 2007)

Increase in caspase-3 activation in colon cancer cells may be caused by antioxidants such as curcumin, (Jaiswal, Marlow et al. 2002) diallyl sulfide (from garlic), (Sriram, Kalayarasan et al. 2008) and the synthetic antioxidant edavarone. (Kokura, Yoshida et al. 2005) Increasing caspase-3 activation means that this enzyme can help control cancer cell growth.

Cyclooxygenase-2 (COX-2)
COX-2 is an enzyme that is involved in the development of colon cancer. COX-2 is also involved in resistance to cell death. COX-2 is correlated with angiogenesis and tumor growth and metastasis. Note that COX-2 is also correlated with normal angiogenesis, such as wound healing. For colon cancer patients, it is beneficial to inhibit COX-2. For example, long-term use of COX-2 inhibitors, which are non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, decreases the risk of colorectal cancer and can regress colorectal polyps in patients with familial adenomatous polyposis. (Bakhle 2001; Sinicrope 2006)

Examples of antioxidants that inhibit COX-2 in colon cancer include curcumin, (Du, Jiang et al. 2006) genistein, (Hwang, Ha et al. 2005) n-3 PUFA from fish oils, and EGCG from green tea. (Hwang, Ha et al. 2007)

c-Myc
c-Myc is a protein that plays an essential role in the regulation of healthy cell growth. Misregulation of this protein occurs in many cancers including colon cancer. (Wierstra and Alves 2008; Robson, Pelengaris et al. 2006)

Curcumin can suppress colon cancer by regulating c-Myc activity. (Jaiswal, Marlow et al. 2002) DHA from fish oil together with 5-fluorouracil can cause colon cancer cell death, which involves c-Myc protein regulation. (Calviello, Di Nicuolo et al. 2005)

Growth Factor Receptors
Epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER-2), and insulin-like growth factor 1 receptor (IGF-1R) are all receptors that are involved in normal cell division and growth. However, when genetic mutations lead to overexpression or overactivity, they are associated with uncontrolled cell division and cancer. (Sibilia, Kroismayr et al. 2007) New cancer therapies are being developed that target these receptors. (Press and Lenz 2007) Cetuximab (Erbitux) is one of these new therapies used in the treatment of metastatic colorectal cancer and this drug works by inhibiting EGFR. The antioxidant curcumin decreases expression and activation of EGFR, HER-2, and 1GF-1R. (Patel, Sengupta et al. 2008)

Glucose Transporter Protein 1 (Glut-1)
Glut-1 is a transporter protein that transports glucose into tissues. It is present in normal cells, but is overly expressed in tumors because tumors require more glucose to meet their increased metabolic needs. In colorectal cancers, expression of Glut-1 has been associated with decreased survival time and more advanced tumors. (Fogt, Wellmann et al. 2001)

The antioxidants EGCG from green tea (Hwang, Ha et al. 2007) and genistein from soy (Hwang, Ha et al. 2005) both decreased Glut-1 in colon cancer cells.

Glutathione S-transferase pi (GSTpi)
GSTpi is part of a family of glutathione S-transferase. Low glutathione S-transferase has been correlated with colon cancer risk. Glutathione S-transferase levels can be increased by eating fruits and vegetables (Grubben, Nagengast et al. 2001) and curcumin. (Chauhan 2002)

Conversely, GSTpi has also been associated with doxorubicin chemotherapy resistance in colon cancer cells. (Takahashi and Niitsu 1994) Lower levels of GSTpi allow doxorubicin to more effectively kill colon cancer cells. Agaricus bisporus lectin, found in the ordinary white button mushroom, is an inhibitor of GSTpi and can increase the effectiveness of several chemotherapy agents in colon cancer. (Goto, Kamada et al. 2002)

Nuclear factor kappa B (NF-kappaB)
Activation of NF-kappaB, a protein complex, is not favorable in cancer treatment. It leads to cellular events that promote inflammation, cell proliferation, angiogenesis, metastasis, and discourages cell death. NF-kappaB is associated with cancer risk, poor prognosis, and contributes to chemotherapy resistance. (Lee, Jeon et al. 2007; Sethi, Sung et al. 2008)

NF-kappaB is activated by many chemotherapeutic compounds and is also inhibited by antioxidants including curcumin, (Hatcher, Planalp et al. 2008) the synthetic antioxidant edavarone, (Kokura, Yoshida et al. 2005) and saponins extracted from ginseng. (Choo, Sakurai et al. 2008) Although diallyl sulfide extracted from garlic increases expression of NF-kappaB, it also showed strong inhibition of cancer cell growth. (Sriram, Kalayarasan et al. 2008)

p53 and p21
p53 is a protein our cells can produce to help suppress the growth of tumors, including colon cancer, and often becomes activated when the DNA has mutations. However, viruses or even other genes can inactivate p53. The gene encoding for p53 may be mutated, particularly in families with a high incidence of cancer, leaving cells more vulnerable to unregulated growth.

p21 is a related protein that is activated by p53 and is also involved in suppressing tumor growth. (Maddika, Ande et al. 2007)

Activation of p53 and p21 in colon cancer has been demonstrated with genistein from soy (Hwang, Ha et al. 2005) and vitamin E. (Chinery, Brockman et al. 1997)

Prostaglandins
Prostaglandins, a group of hormone-like chemicals, promote colon cancer cell growth and are generated by Cox-2 (see Cox-2 on previous page). (Pai, Nakamura et al. 2003)

EGCG from green tea, (Hwang, Ha et al. 2007) genistein from soy (Hwang, Ha et al. 2005) and selenium (Hwang, Kim et al. 2006) can all decrease prostaglandins.

Vascular Endothelial Growth Factor
Vascular Endothelial Growth Factor (VEGF) is an important protein involved in developing a new blood supply such as vasculogenesis (formation of new blood vessels when there are no pre-existing ones) and angiogenesis (formation of new blood vessels from pre-existing ones). In the case of cancer, most tumors require a more extensive blood supply to bring nutrition to support rapid growth. (Veeravagu, Hsu et al. 2007)

EGCG from green tea decreases VEGF. (Hwang, Ha et al. 2007)

5-Fluorouracil

ALPHA-MANGOSTIN
Alpha-Mangostin is a compound found in the pericarp (the tissue surrounding the seed) of the mangosteen fruit. Mangosteen is a tropical evergreen tree that originates from the Malay Archipelago between mainland Southeastern Asia and Australia. Alpha-Mangostin is a powerful antioxidant and has antibiotic, antiviral, and anti-inflammatory activity.

» Mangosteen: Typical doses of mangosteen extract (in capsule or juice form) range from 400 mg to 60,000 mg per day.

In a laboratory study, when alpha-mangostin was combined with 5-fluorouracil (at a concentration of 2.5 µM each), the growth suppression of human colon cancer cells was significantly stronger than 5-fluorouracil treatment alone (at a higher dose of 5 µM). (Nakagawa, Iinuma et al. 2007)

AVEMAR
Avemar is a fermented wheat germ extract developed in Hungary. It supports healthy immune function, inhibits cell proliferation and cell adhesion, enhances apoptosis, and has antioxidant activity.

» Avemar: For an adult of average weight (approximately 155 lbs), a typical daily dose is 9 g, ideally one hour before eating. Patients with a body weight of 200 lbs or more should consume two 9 g doses per day, ideally one hour before breakfast and dinner.

In an animal study using mice with colon cancer, avemar significantly enhanced the anti-metastatic effect of 5-fluorouracil and dacarbazine. Combined treatment decreased toxicity such as weight loss compared to chemotherapy agents administered alone. (Hidvegi, Raso et al. 1999)

CURCUMIN
Curcumin is a polyphenol and is an extract of the Indian curry spice plant turmeric. Curcumin is known for its anti-tumor, antioxidant, anti-amyloid, and anti-inflammatory properties. It also promotes healthy bile excretion and healthy platelet function.

» Curcumin: The best supplements contain curcumin at 75% or higher concentration. Typical doses range from 500 mg to 2,000 mg daily. Take with meals, as curcumin can cause stomach upset when taken on an empty stomach. Bioavailability and potency are increased when combined with bioperine, an extract from black pepper.

In a laboratory study, curcumin was used in combination with 5-fluorouracil in the treatment of human colon cancer cells. This combination proved synergistic. Additionally, COX-2 protein expression was reduced almost six-fold in the combined treatment. (Du, Jiang et al. 2006)

A second laboratory study confirmed the same finding, that curcumin in combination with 5-fluorouracil markedly inhibited the growth of colon cancer cells in comparison to 5-fluorouracil alone. (Kim, Park et al. 2005)

D-GLUCARATE
D-glucarate is a botanical extract from grapefruit, apples, oranges, broccoli, and brussel sprouts. It supports the internal detoxification system called glucuronidation, which makes foreign substances easier to remove from the body. For dietary supplementation, it is combined with calcium to form calcium d-glucarate.

» Calcium D-glucarate: Typical doses range from 50 to 1,000 mg per day.

In a laboratory study with colon tumors from rats, 5-fluorouracil was combined with D-glucarate, which enhanced its effectiveness. (Schmittgen, Koolemans-Beynen et al. 1992)

DIALLYL DISULFIDE (DADS)
Diallyl disulfide (DADS) is a major organosulfur compound found in garlic (Allium sativum) oil.

» Garlic: Typical doses range from 5 to 15 grams per day of whole, fresh garlic and 4,000 to 8,000 micrograms per day of allicin extract.

In an animal study, DADS did not change the effectiveness of 5-fluorouracil treatment in mice with colon tumors. However, the combined treatment significantly reduced chemotherapy-induced side effects such as depressed leukocyte counts, decreased spleen weight, and elevated plasma urea. (Sundaram and Milner 1996)

DOCOSAHEXAENOIC ACID (DHA)
Omega-3 fatty acids come from several different sources and in several different forms. Sources include blue-green algae, fish oil, and eggs. The most active in cancer care are docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). It is used as a supplement in clinical practice for many therapeutic uses, some of which include cancer, heart disease, depression, diabetes, and multiple sclerosis.

» Omega 3 Polyunsaturated fatty acids (PUFA, from fish oil including DHA/EPA): Typical dosage range is from 1,000 mg to 10,000 mg daily. When finding a fish oil supplement, it is important to identify brands that can provide assurance that they’ve tested for heavy metals such as mercury.

DHA enhances colon cancer cell death of four different cell lines together with 5-fluorouracil according to a laboratory study. Concentrations of 5-fluorouracil and DHA used in the study were lower than concentrations typically achieved in patients who are treated with these two agents. 5-fluorouracil inhibited BCL-2 and BCL-XL (types of proteins that enhance tumor cell growth) and induced overexpression of c-Myc. DHA markedly increased these effects, working synergistically with 5-fluorouracil. (Calviello, Di Nicuolo et al. 2005)

EICOSAPENTAENOIC ACID (EPA)
In an animal study using mice, EPA increased the tumor growth inhibition by 5-fluorouracil. It also prevented weight loss normally induced by 5-fluorouracil. (Wynter, Russell et al. 2004)

EPIGALLOCATECHIN-3-GALLATE (EGCG) & GREEN TEA EXTRACT
Epigallocatechin-3-gallate (EGCG) is the principal polyphenol found in green tea.

» EGCG: One cup of green tea contains between 10 and 400 mg of polyphenols depending on the source, amount of leaves used, and steeping time. EGCG may be conveniently obtained from extracts. A good product contains 725 mg, standardized to 98% polyphenols, 45% of which is EGCG.

In a laboratory study, EGCG in combination with 5-fluorouracil or etoposide, reduced colon cancer cell growth more effectively than either 5-fluorouracil or etoposide alone. This study found that EGCG strongly activated AMPK (an enzyme that helps inhibit the growth of some cancers), inhibited COX-2, decreased VEGF (vascular endothelial growth factor), and the glucose transporter Glut-1. (Hwang, Ha et al. 2007)

In a case report series, seven patients with familial polyposis underwent surgery and then received follow up preventive treatment with 5-fluorouracil suppositories and green tea extract. No rectal cancer developed in any of these patients. (Ichikawa, Takahashi et al. 1998)

FISH OIL (DHA/EPA)
In a laboratory study using colon cancer cells, the combined treatment of 5-fluorouracil with fish oil-based lipid emulsion led to significantly more growth inhibition when compared to either treatment alone. (Jordan and Stein 2003)

» Fish Oil: Typical dosages of fish oil range from 1,000 mg to 10,000 mg daily.

GENISTEIN
Genistein is an isoflavone found in legumes, especially soybeans. Isoflavones are antioxidants that counteract the damaging effects of free radicals in body tissues. Isoflavones, such as genistein, also have anti-angiogenic effects, blocking the formation of new blood vessels needed to support the growth of tumors.

» Genistein: A good product will use organic non-GMO genistein. To achieve anti-tumor effects, the target daily dose, based on animal studies and calculations for similar human dosage, is 1500 mg. The recommended dose for furtherresearch is between 100 mg and 1100 mg. (Boik 2001) One cup of soy milk will contain on average about 45 mg of genistein and the other related isoflavones.

When genistein was used together with 5-fluorouracil in the treatment of colon cancer cells in a laboratory study, cell death of colon cancer cells was significantly increased when compared to 5-fluorouracil alone. Investigating the mechanism of this synergistic combination revealed increased activation of AMPK, up-regulation of p53, p21, and Bax, as well as abrogation of the up-regulated state of COX-2 and Glut-1 normally induced by 5-fluorouracil, all of which are ideal for maximum treatment effect. (Hwang, Ha et al. 2005)

GLUTAMINE
Glutamine is a nonessential amino acid. It is necessary for rapidly dividing cells including the intestines and immune system.

» Glutamine: Typical doses range from 500 to 1000 mg per day.

A double blind, randomized controlled trial was conduced to assess whether oral glutamine could prevent intestinal complications of treatment with 5-fluorouracil and folinic acid. Seventy colorectal patients who had not received any chemotherapy prior to the study were enrolled and received either chemotherapy with placebo or chemotherapy with 18 g per day of oral glutamine. Glutamine treatment started five days prior to the beginning of chemotherapy and continued for fifteen days after completion of chemotherapy. The study only covered one chemotherapy cycle, which was given daily for five days.

The reduction of intestinal absorption was more marked in the placebo group and reduction of intestinal permeability was also higher in the placebo group. Average diarrhea was less in the glutamine group and also did not last as long. In the placebo group, one patient developed grade-4 diarrhea (defined as physiological consequences requiring intensive care or haemodynamic collapse) while no patients in the glutamine group developed grade-4 diarrhea. Patients were instructed to take loperamide tablets upon experiencing diarrhea. Patients in the glutamine group consumed less loperamide tablets than the placebo group. This trial thus demonstrated that glutamine protected intestinal mucosa from chemotherapy induced damage. (Daniele, Perrone et al. 2001)

GLUTATHIONE
Glutathione is one of the most powerful and important natural antioxidants produced in the body.

» Glutathione: Typical dosage ranges between 50 mg and 600 mg daily. N-acetyl cysteine is the pre-cursor of glutathione and is more efficiently absorbed. When taking Glutathione or N-acetyl cysteine, combine with three times as much vitamin C. Vitamin C prevents these amino acids from being oxidized in the body and ensures their ability to act as antioxidants.

In a clinical trial with 33 gastric cancer patients and 17 colon cancer patients, intravenous glutathione (1,200 mg per day) was tested in combination with 5-fluorouracil, FT-207 (a different configuration of fluorouracil), and tegafur suppositories. In gastric cancer patients who received glutathione, 5-fluorouracil concentrations in tumors were significantly higher than in patients who did not receive glutathione. However, this effect was not observed in colon cancer patients. (Kitajima, Ikeda et al. 1987)

A laboratory study found that cellular glutathione levels naturally became elevated in human colon cancer cells exposed to 5-fluorouracil for 24 hours. The study found that pretreatment of cancer cells with 5-fluorouracil enhanced the uptake of methotrexate and suggested that the increase in glutathione may have a role in the enhanced methotrexate uptake and cytotoxicity of both chemotherapy drugs. (Chen, Chen et al. 1995)

LENTINAN
Lentinan is a polysaccharide derived from the edible Japanese shiitake mushroom. It possesses immunostimulating antitumor properties.

» Shiitake mushroom extracts: Typical doses range from 100 to 400 mg per day.

In a randomized controlled trial testing lentinan in combination with 5-fluorouracil and mitomycin C or tegafur, a survival advantage was found in advanced or recurrent gastrointestinal cancer patients receiving lentinan. This effect was significant in gastric cancer patients. In colorectal cancer patients, there was also a survival advantage. (Taguchi, Furue, et al. 1985)

N-ACETYL CYSTEINE
N-acetyl cysteine is an efficiently absorbed and used form of the amino acid, L-cysteine. L-cysteine, L-glutamic acid, and glycine are the three amino acids that form glutathione, which is one of the most important and powerful antioxidants in the body.

» N-acetyl cysteine: Typical dosages range between 600 and 1,800 mg per day.

In a laboratory study, N-acetyl cystine augmented apoptosis in combination with 5-fluorouracil in colorectal cancer cell lines. This study found a possible mechanism with induced expression of the pro-apoptotic protein Bax in the treatment combining the two therapies. It was found that neither 5-fluorouracil nor N-acetyl cysteine alone induced an increase in Bax expression, however when combined, Bax expression doubled. (Adeyemo, Imtiaz et al. 2001)

NOTOGINSENG FLOWER EXTRACT
Also known as tianqi and sanqi, notoginseng is a very commonly used Chinese herb for regulating the blood, improving immune function, decreasing fatigue, and improving cognitive, sexual and physical performance.

» Notoginseng: Typical doses range between 250 mg and 1,500 mg daily.

In a laboratory study, notoginseng flower extract significantly increased the anti-proliferation effect of 5-fluorouracil in human colorectal cancer cells. Used as a single agent, 5-fluorouracil inhibited the growth of colon cancer cells by 31.1% and when combined with the notoginseng flower extract, this effect was increased to 59.4%. (Wang, Luo et al. 2007)

URIDINE
Uridine is a nucleoside that can be extracted from sugarcane.

» Uridine: A supplement called NucleomaxX contains 6 g of nucleosides (including uridine) from an extract of sugarcane. The recommended dose is 3 sachets per day, dissolved in water for three consecutive days, once every month.

An animal study used mice with colon cancer both sensitive and resistant to 5-fluorouracil that were treated with the chemotherapy agents 5-fluorouracil and leucovorin. Treatment with uridine (3,500 mg per kg) allowed the use of higher doses of 5-fluorouracil, which improved the antitumor effect on mice that had tumors resistant to 5-fluorouracil. (Nadal, van Groeningen et al. 1989)

VITAMIN E
Vitamin E includes several related compounds: Tocopherols and tocotrienols, each of which have four subtypes of alpha, beta, gamma, and delta. Previously, only alpha-tocopherol was considered important, however each type has unique contributions to health. The best dietary sources of vitamin E are considered to be unrefined, cold-pressed vegetable oils (such as wheat germ, sunflower seed, and olive oils) and raw or sprouted seeds, nuts, and grains.

» Vitamin E: Avoid synthetic vitamin E, such as alpha-tocopherol or succinate. Seek out the mixed tocopherols, including tocopherols and tocotrienols. Typical dosage ranges from 50 IU to 800 IU daily.

In a laboratory study, vitamin E augmented apoptosis in combination with 5-fluorouracil in colorectal cancer cell lines. This study found a possible mechanism with induced expression of the pro-apoptotic protein named Bax in the treatment combining the two therapies. It was found that neither 5-fluorouracil nor vitamin E alone induced an increase in Bax expression, however when combined, Bax expression doubled. (Adeyemo, Imtiaz et al. 2001)

In a laboratory and animal study, the combination of vitamin E and 5-fluorouracil significantly enhanced colorectal cancer tumor growth inhibition in vitro and in vivo. The mechanism by which vitamin E caused apoptosis was by induction of p21, a powerful inhibitor of the cell cycle. (Chinery, Brockman et al. 1997)

Cyclophosphamide

EICOSAPENTAENOIC ACID (EPA)
In an animal study using mice, EPA from fish oil increased the tumor growth inhibition by cyclophosphamide. (Wynter, Russell et al. 2004)

FOLFOX

CURCUMIN
In a laboratory study, curcumin significantly enhanced the inhibition of growth in two different colon cancer cell lines in combination with the FOLFOX chemotherapy regimen. FOLFOX chemotherapy includes leucovorin, 5-fluorouracil, and oxaliplatin. The combination treatment with curcumin decreased activation and expression of epidermal growth factor receptor (EGFR), HER-2 (also known as ErbB-2), and insulin-like growth factor-1 receptor (IGF-1R) and their downstream effectors Akt and cycloxygenase-2. (Patel, Sengupta et al. 2008)

GOSHAJINKIGAN (NIU CHE SHEN QI WAN)
Goshajinkigan is the Japanese name (Niu Che Shen Qi Wan is the Chinese name) for an herbal formula that is used in the treatment of diabetic neuropathy. In a case report from Japan, a 57-year-old woman with advanced stage IV colon cancer underwent surgery and after the operation was given the chemotherapy regimen called FOLFOX 6. The patient took two courses of chemotherapy and grade-2 neurotoxicity developed. The patient was then given the goshajinkigan herbal formula from the third chemotherapy course and the severity of neurotoxicity reduced to grade-1. (Mamiya, Kono et al. 2007)

Gemcitabine

DOCOSAHEXAENOIC ACID (DHA) & EICOSAPENTAENOIC ACID (EPA)
In an animal study using mice, EPA and DHA had no effect on the antitumor effect of gemcitabine. (Wynter, Russell et al. 2004)

Interleukin-2

MELATONIN
Melatonin is a hormone that is released from the pineal gland in the evening and promotes normal sleep; its secretion diminishes significantly with age. It is known to help maintain cell health and many people take it to improve sleep. It is also known to reduce metastasis in cancer patients. In most published studies, melatonin shows a beneficial effect, although it has been reported that in a small proportion of people, melatonin can paradoxically cause sleep disturbance. In others, there can be residual daytime drowsiness, which is usually resolved by using a lower dose.

» Melatonin: Typical dosages range from 1 mg to 20 mg. If aiming for a high dosage, one should start with 1 mg and increase the dosage slowly by 1 mg every 3 to 7 days. The ideal is to achieve peak blood levels of melatonin at about 2am. To do so, one can take the melatonin at bedtime, ideally between 9pm and 10pm.

A clinical trial included 50 metastatic colorectal cancer patients who either had progressed or did not respond to treatment with 5-fluorouracil and folates. Patients were randomized to receive either interleukin-2 (3 million IU per day subcutaneously for 6 days a week for 4 weeks) and melatonin (40 mg per day orally) or supportive care. A partial response was achieved in 3 out of 25 patients treated with interleukin-2 and melatonin whereas no tumor regression occurred in patients receiving only supportive care. Survival at one year was significantly higher in patients treated with interleukin-2 and melatonin (9 out of 25) in comparison to patients receiving only supportive care (3 out of 25). (Barni, Lissoni et al. 1995)

Another clinical trial enrolled 14 metastatic colorectal cancer patients pretreated with 5-fluorouracil. Patients were given low dose interleukin-2 (3 million IU per day for 6 days a week once per day subcutaneously for 4 weeks) with melatonin (50mg per day orally at 8pm). Thirteen patients were evaluable: no tumor regression was seen and stabilized disease was achieved in four patients for a median duration of five months. The other nine patients progressed. (Barni, Lissoni et al. 1992)

Irinotecan

AGARICUS BISPORUS LECTIN
Agaricus bisporus lectin is the active component found in the table mushroom or button mushroom, one of the most widely cultivated mushrooms in the world.

In a laboratory study, agaricus bisporus lectin increase the sensitivity of human colon cancer cells to the treatment of irinotecan, cisplatin, and doxorubicin. No effect was observed when combined with etoposide and 5-fluorouracil. The mechanism thought to underlie this synergism was that agaricus bisporus lectin is an inhibitor of the nuclear transport of glutathione S-transferase (GST) pi. GST pi was found to accumulate in cancer cells in response to chemotherapy and may contribute to drug resistance. (Goto, Kamada et al. 2002)

EDAVARONE
Edavarone is a synthetic antioxidant. We report its use here to demonstrate how pharmaceutical companies are investigating antioxidants (that can be patented) in combination with chemotherapy, while physicians continue warning about natural antioxidant use.

» Edavarone: Edavarone (trade name Radicut) is a free-radical scavenger manufactured in Japan and used primarily in the treatment of acute stroke.

In a laboratory study, edaravone enhanced the treatment effect of irinotecan in human colon cancer cells. The mechanism included inhibition of NF-kappaB and also enhanced activation of caspase-3. Irinotecan also activated caspase-3 and in contrast to edaravone activated NF-kB. Edaravone scavenged the reactive oxygen species induced by irinotecan and, according to conventional wisdom and the current stance on antioxidants in combination with chemotherapy, this should mean edavarone would decrease treatment effect of ironotecan. To the contrary, however, the combination is synergistic, meaning there was a beneficial enhancement of the therapeutic effect of irinotecan. The study continued in vivo, where irinotecan combined with edaravone reduced subcutaneous tumor growth and pulmonary metastases more than irinotecan treatment alone. (Kokura, Yoshida et al. 2005)

MELATONIN
A clinical trial investigated combined treatment of irinotecan and melatonin. Thirty metastatic colorectal cancer patients, who had progressed after at least one chemotherapy treatment including 5-fluorouracil, were randomized to treatment with irinotecan alone or irinotecan (125 mg per m2 weekly, administered intravenously) plus melatonin (20 mg per day taken orally, in the evening) for nine consecutive weeks of treatment. There was no complete response. Partial responses occurred in 2 out of 16 patients receiving ironotecan alone and in 5 out of 14 patients also receiving melatonin. Stable disease occurred in 5 out of 16 patients receiving ironotecan alone and in 7 out of 14 patients also receiving melatonin. Disease control in patients receiving ironotecan alone was 7 out of 16 and 12 out of 14 in patients also receiving melatonin. This is a significantly higher percentage of disease control for patients receiving a combination of ironotecan and melatonin. Diarrhea of grade 3-4 occurred in 6 out of 16 patients treated with irinotecan alone and in 4 out of 14 patients treated with irinotecan plus melatonin and required a 50% dose reduction. Disease control was similar in patients who received full dose of chemotherapy and those receiving a reduced dose. (Cerea, Vaghi et al. 2003)

SELENIUM
Selenium is an essential trace mineral in the body and is found in variable amounts in food depending on the soil content of selenium. Brazil nuts are the single best food source of selenium. One of its roles in the body is as an antioxidant and it is most widely known as a cancer preventive.

» Selenium (mineral): The US adult Tolerable Upper Intake Level (UL) is 400 micrograms a day and the Lowest Observed Adverse Effects Level (LOAEL) for adults is about 900 micrograms daily. There are several different forms of selenium. Se-Methylselenocysteine is a highly bioavailable form because it is not incorporated within a protein such as the form selenomethionine. We recommend getting selenium either in the organically bound forms such as of Se-Methylselenocysteine or a combination of selenium compounds with L-selenomethionine, sodium selenate, selenodiglutathione, and Se-methylselenocysteine.

An animal study using mice with colon cancer types that are sensitive and resistant to chemotherapy tested the selenium compounds 5-methylselenocysteine and seleno-L-methionine together with various chemotherapy agents including irinotecan. Selenium was highly protective against toxicity induced by various chemotherapy agents including 5-fuorouracil, cisplatin, oxaliplatin, paclitaxel, and doxorubicin. The effect of selenium on treatment effectiveness was measured only with irinotecan. In combination with the maximum tolerated dose of irinotecan, selenium (administered seven days prior to chemotherapy and continuing throughout chemotherapy treatment) significantly increased the cure rates of mice with colon cancer tumors that are sensitive and resistant to irinotecan. For example, in tumors resistant to irinotecan treatment with ironotecan alone lead to a cure rate of 0%. When combined with selenium, the cure rate rose to 20%. In tumors that were sensitive to ironotecan, whereas treatment with ironotecan alone showed a cure rate of 20%, irinotecan combined with selenium showed a cure rate of an astonishing 100%. Selenium combined with chemotherapy treatment was also effective in preventing weight loss. (Cao, Durrani et al. 2004)

Oxaliplatin, 5-Fluorouracil, and Leucovorin

CALCIUM GLUCONATE & MAGNESIUM SULFATE
Calcium gluconate is a mineral that is found naturally in foods such as almonds, sesame seeds, dark green leafy vegetables, milk, and yogurt. Calcium (Ca) is needed for many bodily functions, especially bone formation. Calcium can bind to other minerals and aid in removal from the body. Calcium gluconate is used to prevent and treat calcium deficiencies.

Magnesium (Mg) is a mineral that is present in many foods, including almonds, cashews, soybeans, buckwheat, and wheat bran. Magnesium helps maintain normal nerve and muscle function, keeps the heart rhythm steady, keeps bones strong, and supports the immune system. Magnesium sulfate is one form of magnesium supplements.

A retrospective cohort study from France included 161 colorectal cancer patients. 65 patients received chemotherapy alone and 96 patients received intravenous infusions of calcium gluconate and magnesium sulfate (1 g each) delivered over 15 minutes prior to chemotherapy. Chemotherapy treatment consisted of oxaliplatin, 5-fluorouracil, and leucovorin. The FOLFOX 4 regimen (oxaliplatin 85 mg per m2 every two weeks), FOLFOX 6 (oxaliplatin 100 mg per m2 every two weeks), and FUFOX (130 mg per m2 every three weeks) were used. Tumor response and toxicity were evaluated. Treatment efficacy was evaluated three months after the beginning of treatment. The number of patients receiving FUFOX regimen were similar, 42 receiving CaMg and 43 receiving chemotherapy alone. The other regimens had unequal numbers of patients either receiving CaMg or not, therefore this study only collected data on treatment efficacy in the FUFOX group.

Treatment efficacy: Both the number of treatment cycles and the mean cumulative oxaliplatin doses were higher in patients treated with CaMg compared to patients receiving chemotherapy alone, however the difference was not statistically significant. After 12 cycles of chemotherapy, the percentage of patients remaining in treatment was greater in patients receiving CaMg. This was seen most pronounced in patients receiving the FOLFOX 6 regimen where 36% of patients remained receiving CaMg and 11% remained receiving chemotherapy alone. The response rate was 45% in patients receiving CaMg and 35% in patients receiving chemotherapy alone.

No CaMg induced toxicity was observed. At the end of treatment, 20% of patients receiving CaMg had neuropathy compared to 45% of patients receiving chemotherapy alone. The percentage of patients who withdrew from treatment due to any toxicity was 33% in patients receiving CaMg and 51% in patients receiving chemotherapy alone. The percentage of patients who withdrew due to neurotoxicity was only 4% in patients receiving CaMg and 31% in patients receiving chemotherapy alone. The percentage of patients who withdrew due to grade 3 chronic neurotoxicity was 0% in patients receiving CaMg and 12% in patients receiving chemotherapy alone. With regard to chronic neuropathy at the end of treatment, 65% of patients receiving CaMg had no neuropathy and only 37% receiving chemotherapy alone did not have neuropathy. The duration of neuropathy equal or greater than 2 was longer in patients receiving chemotherapy alone. For example, patients on the FOLFOX 4 chemotherapy regimen receiving CaMg had neuropathy lasting two months, and patients receiving chemotherapy alone for 12 months. Chronic grade 3 neuropathy at the end of treatment was 8% in patients receiving CaMg and 20% in patients receiving chemotherapy alone. Grade 3 neuropathy is defined by the National Cancer Institute as “paresthesia interfering with function, severe objective sensory loss” and in the case specific to oxaliplatin as “paresthesia, dysesthesia causing functional impairment.”

Other chemotherapy-induced toxicities were also mitigated. Diarrhea greater or equal to grade 2 occurred in only 10% percent of chemotherapy cycles for patients receiving CaMg, and 27% for patients receiving chemotherapy alone. Asthenia greater or equal to grade 2 occurred in only 13% percent of chemotherapy cycles for patients receiving CaMg and 41% for patients receiving chemotherapy alone. Stable weight was 92% in patients receiving CaMg and only 75% in patients receiving chemotherapy alone. (Gamelin, Boisdron-Celle et al. 2004)

An encouraging case report emerged a few years later showing how a protocol using calcium gluconate and magnesium sulfate helped a woman continue chemotherapy. A 40-year-old woman had 4 out of 6 weeks of one cycle of the FLOX chemotherapy regimen (500 mg per m2 5-fluorouracil weekly, 500 mg per m2 folinic acid and 85 mg per m2 oxaliplatin). During the first infusion of oxaliplatin, she experienced severe nausea and vomiting as well as a headache and loss of vision in her right eye, which resolved in 24 hours. The administration of the second dose of oxaliplatin was extended to three hours, however she developed severe chest pain, headache and loss of vision, for which she received diphenhydramine and hydrocortisone and recovered in the emergency room with intravenous support.

Then the patient was referred to Yale New Haven Hospital (Yale University School of Medicine) where she received intravenous calcium gluconate 1 g and magnesium sulfate 1 g prior to and following the FOLFOX 6 chemotherapy regimen. Prior to chemotherapy she also received famotidine, diphenhydramine, ondansetron, and decadron. The patient did not develop any of the side effects that she experienced during the prior treatments with oxaliplatin. She successfully completed nine cycles of FOLFOX 6 using the same medications mentioned previously. (Wrzesinski, McGurk et al. 2007)

GLUTATHIONE
A randomized, double-blind, placebo-controlled clinical trial was conducted to assess glutathione in the prevention of neurotoxicity induced by oxaliplatin-based chemotherapy. Fifty-two patients with advanced colorectal cancer were enrolled: 26 patients received chemotherapy (oxaliplatin, 5-fluorouracil, and leucovorin) with normal saline solution (as a placebo) and 26 patients received the same chemotherapy with glutathione (1,500 mg per m2). Evaluations of neurotoxicity were performed at baseline and after 4, 8, and 12 cycles of treatment.

After the fourth chemotherapy cycle, 7 out of 26 patients in the GSH group had neuropathy (grade 1-2) and 11 out of 26 patients in the placebo group had neuropathy (grade 1-2). After the eighth cycle, 9 out of 21 evaluable patients in the GSH group had neuropathy (grade 1-2). The nineteen evaluable patients in the placebo group didn’t fare as well, with 10 patients having grade 1-2 neuropathy and 5 patients having grade 3-4 neuropathy. After twelve cycles, 8 out of 10 evaluable patients in the GSH group had grade 1-2 neuropathy and one patient had grade 3 neuropathy. In the placebo group, 2 out of 8 evaluable patients had grade 1-2 neuropathy and 6 patients had grade 3-4 neuropathy.

After eight cycles, 11 out of 19 patients in the placebo group and only 2 out of 21 patients in the GSH group had grade 2-4 neuropathy. After 12 cycles, 8 out of 8 patients in the placebo arm and only 3 out of 10 in the GSH arm had grade 2-4 neuropathy. Sural sensory nerve conduction was reduced significantly in the placebo group but not in the GSH group. The overall response rate to treatment was slightly higher in the GSH group at 26.9% and was 23.1% in the placebo arm, thus showing no reduction in the efficacy of chemotherapy treatment. This study provides evidence that GSH is promising as a therapy for the prevention of oxaliplatin-induced neuropathy, and that GSH does not interfere with the anti-tumor effect of this chemotherapy regimen. (Cascinu, Catalano et al. 2002; Arnould, Hennebelle et al. 2003)

N-ACETYL CYSTEINE
Fourteen stage III colon cancer patients were enrolled in a clinical trial to assess whether oral N-acetyl cysteine could reduce neurotoxicity induced by a chemotherapy regimen including oxaliplatin, 5-fluorouracil, and low dose leucovorin. Five patients (group-A) received a combination of chemotherapy and N-acetyl cysteine (1,200 mg). Nine patients (group-B) received chemotherapy alone. Evaluations were made at the onset of treatment and after 4, 8, and 12 treatment cycles. After four cycles of chemotherapy, 40% in group-A had grade 1 neuropathy compared to 77.8% in group-B. After eight cycles of chemotherapy, 60% in group-A had grade 1 neuropathy and none had a higher grade of neuropathy. In contrast, patients in group-B began to develop higher grades of neuropathy, with 44.4% still at grade 1, but 55.6% now progressed to grade 2 neuropathy. After twelve cycles of chemotherapy, 60% in group-A had grade 1 neuropathy and 20% had grade 2 neuropathy. In group-B, 11.1% had grade 1 neuropathy, 55.6% had grade 2 neuropathy, and 33.3% developed grade 3 neuropathy. Therefore patients receiving N-acetyl cysteine developed significantly less neuropathy. (Lin, Lee et al. 2006)

Tegafur

N-ACETYL CYSTEINE
N-acetyl cysteine did not significantly alter the activity of tegafur in colon cancer cells. However, N-acetyl cysteine did reduce the effectiveness of a very new drug that is a derivative of tegafur, called butyroyloxymethyl-tegafur derivative 3. (Engel, Nudelman et al. 2008)

POLYSACCHARIDE-K (PSK)
Polysaccharide-K (PSK) is extracted from a mushroom called turkey tail. Other names include Trametes versicolor and Coriolus versicolor (Latin), yun zhi (Chinese), and kawaratake (Japanese). It is commonly used to boost immune health and often used with cancer patients.

» PSK: Typical doses for cancer patients range between 2 to 6 g.

In an animal study, the chemotherapy combination of tegafur (Uracil) (UFT) plus leucovorin (LV) was weakly effective with colon cancer. The addition of PSK did not make the anti-tumor treatment any more or less effective. The same was true for Lewis lung cancer. However, in Meth A sarcoma, PSK did enhance this chemotherapy regimen. (Katoh and Ooshiro 2007)

Paclitaxel

COMBINATIONS TO AVOID: N-ACETYL CYSTEINE
In an animal study using mice with colon cancer, N-acetyl cysteine interfered with the anti-tumor activity of paclitaxel when used in combination. However N-acetyl cysteine did prevent toxicity to blood cells due to paclitaxel. Because this study reports that N-acetyl cysteine can reduce effectiveness of paclitaxel, we recommend not using this combination. (Alexandre, Nicco et al. 2006)

Pemetrexed

FOLIC ACID AND VITAMIN B12
Vitamin B12, also known as cobalamins, can be found in various dietary sources, including liver, meat, eggs, milk, and saltwater fish.

» Vitamin B12: Typical adult doses range from 1 to 3 micrograms per day.

Folic acid, also known as vitamin B9, is found in dietary sources such as dark leafy green vegetables, liver, egg yolk, various beans, and peas.

» Vitamin B9: Typical adult doses range from 300 micrograms to no more than 900 micrograms per day.

In the earlier stages of developing pemetrexed as a treatment for cancer (mostly used for malignant pleural mesothelioma and non-small cell lung cancer, but having activity against colon cancer as well), life threatening toxicities were encountered. It was soon discovered that supplementation with folic acid and vitamin B12 could minimize these toxicities when included in the treatment regimen. (Curtin and Hughes 2001; Scagliotti and Novello 2003)

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REFERENCES AND SELECT STUDY ABSTRACTS

Adams, J. M. and S. Cory (2007). “Bcl-2-regulated apoptosis: mechanism and therapeutic potential.” Curr Opin Immunol 19(5): 488-96.

Apoptosis is essential for tissue homeostasis, particularly in the hematopoietic compartment, where its impairment can elicit neoplastic or autoimmune diseases. Whether stressed cells live or die is largely determined by interplay between opposing members of the Bcl-2 protein family. Bcl-2 and its closest homologs promote cell survival, but two other factions promote apoptosis. The BH3-only proteins sense and relay stress signals, but commitment to apoptosis requires Bax or Bak. The BH3-only proteins appear to activate Bax and Bak indirectly, by engaging and neutralizing their pro-survival relatives, which otherwise constrain Bax and Bak from permeabilizing mitochondria. The Bcl-2 family may also regulate autophagy and mitochondrial fission/fusion. Its pro-survival members are attractive therapeutic targets in cancer and perhaps autoimmunity and viral infections.

Adeyemo, D., F. Imtiaz, et al. (2001). “Antioxidants enhance the susceptibility of colon carcinoma cells to 5-fluorouracil by augmenting the induction of the bax protein.” Cancer Lett 164(1): 77-84.

5 Fluorouracil (5 FU), the most effective systemic chemotherapeutic agent in the management of advanced colorectal carcinoma acts by inducing apoptosis. Response rates, approximately 20% is improved by folinic acid. This study investigates similar modulation of 5 FU-induced apoptosis by oxidant quenching. A five-fold reduction of intracellular oxidant levels by antioxidants N-acetylcysteine and vitamin E did not induce apoptosis, it however augmented pro-apoptotic bax protein expression, and apoptotic response to a non-toxic dose of 5 FU in the colorectal cancer cell lines colo 201 and colo 205. This suggests that reduction of intracellular levels of reactive oxygen species enhance susceptibility to 5 FU (apoptotic stimuli) by augmentation of bax expression.

Alexandre, J., C. Nicco, et al. (2006). “Improvement of the therapeutic index of anticancer drugs by the superoxide dismutase mimic mangafodipir.” J Natl Cancer Inst 98(4): 236-44.

BACKGROUND: Anticancer drugs act by increasing intracellular hydrogen peroxide levels. Mangafodipir, a superoxide dismutase (SOD) mimic with catalase and glutathione reductase activities, protects normal cells from apoptosis induced by H2O2. We investigated its and other oxidative stress modulators’ effects on anticancer drug activity in vitro and in vivo. METHODS: Cell lysis and intracellular reactive oxygen species levels were assessed in vitro in human leukocytes from healthy subjects and in murine CT26 colon cancer cells. Cells were exposed to the chemotherapeutic agents paclitaxel, oxaliplatin, or 5-fluorouracil, either in the presence or absence of mangafodipir and other oxidative stress modulators. Cell viability was evaluated by the methylthiazoletetrazolium assay. The effects of mangafodipir and other oxidative stress modulators on peripheral blood counts and on tumor growth were studied in BALB/c mice that were implanted with CT26 tumors and treated with 20 mg/kg paclitaxel. Survival of BALB/c mice infected with Staphylococcus aureus was also examined by treatment group. Statistical tests were two-sided. RESULTS: In vitro lysis of leukocytes exposed to paclitaxel, oxaliplatin, or 5-fluorouracil in combination with mangafodipir was decreased by 46% (95% confidence interval [CI] = 44% to 48%), 30.5% (95% CI = 29% to 32%), and 15% (95% CI = 10% to 20%), compared with lysis of cells treated with anticancer agent alone. Mangafodipir also statistically significantly enhanced in vitro anticancer drug cytotoxicity toward CT26 cancer cells. In vivo, mangafodipir protected mice against paclitaxel-induced leukopenia. Moreover, the survival rate of mice infected with S. aureus and treated with paclitaxel was higher when mangafodipir was also administered (survival: 3 of 17 versus 14 of 17, P < .001). In addition, mangafodipir amplified the inhibitory effect of paclitaxel on CT26 tumor growth in mice. CONCLUSIONS: Mangafodipir decreased hematotoxicity and enhanced cytotoxicity of anticancer agents.

Arnould, S., I. Hennebelle, et al. (2003). “Cellular determinants of oxaliplatin sensitivity in colon cancer cell lines.” Eur J Cancer 39(1): 112-9.

Oxaliplatin (L-OHP) is a new platinum analogue that has shown antitumour activity against colon cancer both in vitro and in vivo and is now used in the chemotherapeutic treatment of metastatic colon and rectal cancer. L-OHP like cisplatin (CDDP), is detoxified by glutathione (GSH)-related enzymes and forms platinum (Pt)-DNA adducts lesions that are repaired by the nucleotide excision repair system (NER). We investigated the cytotoxicity and the pharmacology of L-OHP and CDDP on a panel of six colon cell lines in vitro. We showed that GSH and glutathione S-transferase (GST) activity were not correlated to oxaliplatin cytotoxicity. Pt-DNA adducts formation and repair were correlated with CDDP, but not with L-OHP cytotoxicity. The determination of ERCC1 and XPA expression, two enzymes of the NER pathway, by reverse transcriptase-polymerase chain reaction (RT-PCR), demonstrated that ERCC1 expression was predictive of L-OHP sensitivity (r(2)=0.67, P=0.02) and XPA level after oxaliplatin exposure was also correlated to L-OHP IC(50) (r(2)=0.5; P=0.04). The knowledge of such correlations could help predict the sensitivity of patients with colon cancer to L-OHP.

Bakhle, Y. S. (2001). “COX-2 and cancer: a new approach to an old problem.” Br J Pharmacol 134(6): 1137-50.

Barni, S., P. Lissoni, et al. (1995). “A randomized study of low-dose subcutaneous interleukin-2 plus melatonin versus supportive care alone in metastatic colorectal cancer patients progressing under 5-fluorouracil and folates.” Oncology 52(3): 243-5.

Chemotherapy with 5-fluorouracil (5-FU) and folates represents the first-line standard therapy for metastatic colorectal cancer, whereas at present there is no conventional second-time treatment. Because of its importance in generating an effective anticancer immune response, interleukin-2 (IL-2) could constitute a new promising therapy of advanced colon cancer. Generally, IL-2 may determine tumor regressions in colon cancer only when it is given at high toxic doses. Our preliminary studies have shown that the pineal hormone melatonin may amplify IL-2 activity, which becomes active also at low doses in several tumor histotypes. On the basis, we have performed a clinical trial to evaluate the impact of low-dose IL-2 plus melatonin on the survival time in metastatic colon cancer, which progressed in response to 5-FU plus folates. The study included 50 metastatic colorectal cancer patients, who did not respond or progressed after initial response to first-line chemotherapy with 5-FU and folates. Patients were randomized to receive supportive care alone or low-dose subcutaneous IL-2 (3 million IU/day for 6 days/week for 4 weeks) plus melatonin (40 mg/day orally). No spontaneous tumor regression occurred in patients receiving supportive care alone. A partial response was achieved in 3/25 patients treated with immunotherapy. Percent survival at 1 year was significantly higher in patients treated with immunotherapy than in those treated with supportive care alone (9/25 vs. 3/25, p < 0.05). This study suggests that low-dose subcutaneous IL-2 plus melatonin may be effective as a second-line therapy to induce tumor regression and to prolong percent survival at 1 year in metastatic colorectal cancer patients progressing under 5-FU and folates.

Barni, S., P. Lissoni, et al. (1992). “Neuroimmunotherapy with subcutaneous low-dose interleukin-2 and the pineal hormone melatonin as a second-line treatment in metastatic colorectal carcinoma.” Tumori 78(6): 383-7.

On the basis of our previous preliminary data which showed that the pineal hormone melatonin (MLT) may potentiate IL-2 activity and reduce the dose of IL-2 required to determine an effective host antitumor response, we performed a clinical study with low-dose IL-2 given once/day subcutaneously (3 million IU/day for 6 days/week for 4 weeks) in association with MLT (50 mg/day orally at 8.00 p.m. every day) as a second-line therapy in metastatic colorectal cancer patients pretreated with 5-fluorouracil. Evaluable patients were 13/14, and most of them showed disseminated liver metastases. No objective tumor regression was seen. A stabilization of disease was achieved in 4/13 patients (median duration 5+ months), and the other 9 patients progressed. Mean number of lymphocytes and eosinophils significantly increased during the treatment. Moreover, the mean increase in lymphocyte number was significantly higher in patients with stable disease than in those with progressive disease, whereas there was no difference as regards eosinophils. Serum levels of neopterin and tumor necrosis factor (TNF) significantly increased during therapy, and TNF increase was correlated to the side effects rather than to the control of cancer development. This study shows that neuroimmunotherapy with low-dose interleukin-2 and MLT, even though capable of determining an evident expansion of immune cells involved in host antitumor response, does not seem to be effective in terms of tumor regression in metastatic colon cancer patients pretreated with 5-fluorouracil.

Calviello, G., F. Di Nicuolo, et al. (2005). “Docosahexaenoic acid enhances the susceptibility of human colorectal cancer cells to 5-fluorouracil.” Cancer Chemother Pharmacol 55(1): 12-20.

PURPOSE: Powerful growth-inhibitory action has been shown for n-3 polyunsaturated fatty acids against colon cancer cells. We have previously described their ability to inhibit proliferation of colon epithelial cells in patients at high risk of colon cancer. In the work reported here we investigated the ability of docosahexaenoic acid (DHA) to potentiate the antineoplastic activity of 5-fluorouracil (5-FU) in p53-wildtype (LS-174 and Colo 320) and p53-mutant (HT-29 and Colo 205) human colon cancer cells. METHODS: When in combination with DHA, 5-FU was used at concentrations ranging from 0.1 to 1.0 microM, much lower than those currently found in plasma patients after infusion of this drug. Similarly, the DHA concentrations (< or =10 microM) used in combination with 5-FU were lower than those widely used in vitro and known to cause peroxidative effects in vivo. RESULTS: Whereas the cells showed different sensitivity to the growth-inhibitory action of 5-FU, DHA reduced cell growth independently of p53 cellular status. DHA synergized with 5-FU in reducing colon cancer cell growth. The potentiating effect of DHA was attributable to the enhancement of the proapoptotic effect of 5-FU. DHA markedly increased the inhibitory effect of 5-FU on the expression of the antiapoptotic proteins BCL-2 and BCL-XL, and induced overexpression of c-MYC which has recently been shown to drive apoptosis and, when overexpressed, to sensitize cancer cells to the action of proapoptotic agents, including 5-FU. CONCLUSION: Our results indicate that DHA strongly increases the antineoplastic effects of low concentrations of 5-FU. Overall, the results suggest that combinations of low doses of the two compounds could represent a chemotherapeutic approach with low toxicity.

Cao, S., F. A. Durrani, et al. (2004). “Selective modulation of the therapeutic efficacy of anticancer drugs by selenium containing compounds against human tumor xenografts.” Clin Cancer Res 10(7): 2561-9.

PURPOSE: Studies were carried out in athymic nude mice bearing human squamous cell carcinoma of the head and neck (FaDu and A253) and colon carcinoma (HCT-8 and HT-29) xenografts to evaluate the potential role of selenium-containing compounds as selective modulators of the toxicity and antitumor activity of selected anticancer drugs with particular emphasis on irinotecan, a topoisomerase I poison. EXPERIMENTAL DESIGN: Antitumor activity and toxicity were evaluated using nontoxic doses (0.2 mg/mouse/day) and schedule (14-28 days) of the selenium-containing compounds, 5-methylselenocysteine and seleno-L-methionine, administered orally to nude mice daily for 7 days before i.v. administration of anticancer drugs, with continued selenium treatment for 7-21 days, depending on anticancer drugs under evaluation. Several doses of anticancer drugs were used, including the maximum tolerated dose (MTD) and toxic doses. Although many chemotherapeutic agents were evaluated for toxicity protection by selenium, data on antitumor activity were primarily obtained using the MTD, 2 x MTD, and 3 x MTD of weekly x4 schedule of irinotecan. RESULTS: Selenium was highly protective against toxicity induced by a variety of chemotherapeutic agents. Furthermore, selenium increased significantly the cure rate of xenografts bearing human tumors that are sensitive (HCT-8 and FaDu) and resistant (HT-29 and A253) to irinotecan. The high cure rate (100%) was achieved in nude mice bearing HCT-8 and FaDu xenografts treated with the MTD of irinotecan (100 mg/kg/week x 4) when combined with selenium. Administration of higher doses of irinotecan (200 and 300 mg/kg/week x 4) was required to achieve high cure rate for HT-29 and A253 xenografts. Administration of these higher doses was possible due to selective protection of normal tissues by selenium. Thus, the use of selenium as selective modulator of the therapeutic efficacy of anticancer drugs is new and novel. CONCLUSIONS: We demonstrated that selenium is a highly effective modulator of the therapeutic efficacy and selectivity of anticancer drugs in nude mice bearing human tumor xenografts of colon carcinoma and squamous cell carcinoma of the head and neck. The observed in vivo synergic interaction is highly dependent on the schedule of selenium.

Cascinu, S., V. Catalano, et al. (2002). “Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: a randomized, double-blind, placebo-controlled trial.” J Clin Oncol 20(16): 3478-83.

PURPOSE: We performed a randomized, double-blind, placebo-controlled trial to assess the efficacy of glutathione (GSH) in the prevention of oxaliplatin-induced neurotoxicity. PATIENTS AND METHODS: Fifty-two patients treated with a bimonthly oxaliplatin-based regimen were randomized to receive GSH (1,500 mg/m(2) over a 15-minute infusion period before oxaliplatin) or normal saline solution. Clinical neurologic evaluation and electrophysiologic investigations were performed at baseline and after four (oxaliplatin dose, 400 mg/m(2)), eight (oxaliplatin dose, 800 mg/m(2)), and 12 (oxaliplatin dose, 1,200 mg/m(2)) cycles of treatment. RESULTS: At the fourth cycle, seven patients showed clinically evident neuropathy in the GSH arm, whereas 11 patients in the placebo arm did. After the eighth cycle, nine of 21 assessable patients in the GSH arm suffered from neurotoxicity compared with 15 of 19 in the placebo arm. With regard to grade 2 to 4 National Cancer Institute common toxicity criteria, 11 patients experienced neuropathy in the placebo arm compared with only two patients in the GSH arm (P =.003). After 12 cycles, grade 2 to 4 neurotoxicity was observed in three patients in the GSH arm and in eight patients in the placebo arm (P =.004). The neurophysiologic investigations (sural sensory nerve conduction) showed a statistically significant reduction of the values in the placebo arm but not in the GSH arm. The response rate was 26.9% in the GSH arm and 23.1% in the placebo arm, showing no reduction in activity of oxaliplatin. CONCLUSION: This study provides evidence that GSH is a promising drug for the prevention of oxaliplatin-induced neuropathy, and that it does not reduce the clinical activity of oxaliplatin.

Cerea, G., M. Vaghi, et al. (2003). “Biomodulation of cancer chemotherapy for metastatic colorectal cancer: a randomized study of weekly low-dose irinotecan alone versus irinotecan plus the oncostatic pineal hormone melatonin in metastatic colorectal cancer patients progressing on 5-fluorouracil-containing combinations.” Anticancer Res 23(2C): 1951-4.

Recent advances in immunobiological knowledge have suggested the possibility of enhancing the therapeutic activity of various chemotherapeutic agents by a concomitant administration of anti-oxidant drugs and/or immunomodulating neurohormones. In particular, the pineal neurohormone melatonin (MLT), which is able to exert both antioxidant and immunomodulating effects, has been proven to enhance the efficacy of various chemotherapeutic drugs, namely cisplatin, anthracyclines and 5-fluorouracil, whereas at present there are no data about its possible influence on cytotoxic drugs effective in the treatment of colon cancer other than 5-fluorouracil, such as irinotecan (CPT-11). The present study was performed to evaluate the influence of a concomitant administration of MLT on CPT-11 therapeutic activity in metastatic colorectal cancer. The study included 30 metastatic colorectal cancer patients progressing after at least one previous chemotherapeutic line containing 5-fluorouracil, who were randomized to be treated with CPT-11 alone or CPT-11 plus MLT. According to a weekly low-dose schedule, CPT-11 was given i.v. at 125 mg/m2/week for 9 consecutive weeks. MLT was administered orally at 20 mg/day during the dark period of the day. No complete response was observed. A partial response (PR) was achieved in 2 out of 16 patients treated with CPT-11 alone and in 5 out of 14 patients concomitantly treated with MLT. Moreover, a stable disease (SD) was obtained in 5 out of 16 patients treated with CPT-11 alone and in 7 out of 14 patients treated with CPT-11 plus MLT. Therefore, the percent of disease-control achieved in patients concomitantly treated with MLT was significantly higher than that observed in those treated with chemotherapy alone (12 out of 14 vs 7 out of 16, p < 0.05). The only important toxicity was diarrhoea grade 3-4, which occurred in 6 out of 16 patients treated with CPT-11 alone and in 4 out of 14 patients treated with CPT-11 plus MLT, which required a 50% dose reduction. However, taken together, patients treated with CPT-11 at 50% of the planned dose showed a percent of disease control comparable to that achieved in patients who had no dose reduction (6 out of 10 vs 13 out of 20). This preliminary study shows that the efficacy of weekly low-dose CPT-11 in pretreated metastatic colorectal cancer patients may be enhanced by a concomitant daily administration of the pineal hormone MLT, according to the results previously reported for other chemotherapeutic agents. Moreover, since the dose reduction of CPT-11 does not influence its efficacy, the dose of CPT-11 for successive studies might be not greater than 70 mg/m2.

Chauhan, D. P. (2002). “Chemotherapeutic potential of curcumin for colorectal cancer.” Curr Pharm Des 8(19): 1695-706.

Colorectal cancer is one of the leading causes of cancer deaths in the Western world. More than 56,000 newly diagnosed colorectal cancer patients die each year in the United States. Available therapies are either not effective or have unwanted side effects. Epidemiological data suggest that dietary manipulations play an important role in the prevention of many human cancers. Curcumin the yellow pigment in turmeric has been widely used for centuries in the Asian countries without any toxic effects. Epidemiological data also suggest that curcumin may be responsible for the lower rate of colorectal cancer in these countries. Curcumin is a naturally occurring powerful anti-inflammatory medicine. The anticancer properties of curcumin have been shown in cultured cells and animal studies. Curcumin inhibits lipooxygenase activity and is a specific inhibitor of cyclooxygenase-2 expression. Curcumin inhibits the initiation of carcinogenesis by inhibiting the cytochrome P-450 enzyme activity and increasing the levels of glutathione-S-transferase. Curcumin inhibits the promotion/progression stages of carcinogenesis. The anti-tumor effect of curcumin has been attributed in part to the arrest of cancer cells in S, G2/M cell cycle phase and induction of apoptosis. Curcumin inhibits the growth of DNA mismatch repair defective colon cancer cells. Therefore, curcumin may have value as a safe chemotherapeutic agent for the treatment of tumors exhibiting DNA mismatch repair deficient and microsatellite instable phenotype. Curcumin should be considered as a safe, non-toxic and easy to use chemotherapeutic agent for colorectal cancers arise in the setting of chromosomal instability as well as microsatellite instability.

Chen, M. F., L. T. Chen, et al. (1995). “Effect of 5-fluorouracil on methotrexate transport and cytotoxicity in HT29 colon adenocarcinoma cells.” Cancer Lett 88(2): 133-40.

Exposure of the human colon adenocarcinoma HT29 cells to different concentrations of 5-fluorouracil (5FU) for 24 h resulted in a dose-dependent increase in the cellular glutathione (GSH) level which remained elevated up to 72 h following 5FU treatment. Pretreatment of HT29 cells with 5FU was found to enhance the uptake of methotrexate (MTX) as compared to control cells. Administration of MTX 24 h after 5FU was found to be synergistic, whereas administration of MTX 24 h before 5FU or together with 5FU was not found to be synergistic. The results of this study suggest that the increase in cellular GSH level as a result of 5FU pretreatment may play a role in the enhancement of MTX uptake and the cytotoxicity of both drugs in HT29 cells.

Chen, M. F., L. T. Chen, et al. (1995). “5-Fluorouracil cytotoxicity in human colon HT-29 cells with moderately increased or decreased cellular glutathione level.” Anticancer Res 15(1): 163-7.

Little is known whether diet or certain components in the diet can modulate the efficacy of 5-fluorouracil (5FU) in patients with colon carcinoma. Glutathione (GSH), an important antioxidant and anticarcinogen, is present in many foods in varying amounts. This study examined whether a moderately increased or decreased cellular GSH level had any effect on the growth of human colon adenocarcinoma cells HT-29 and on the cytotoxic activity of 5FU in these cells. GSH and buthionine sulfoximine were used to enhance or reduce the GSH level respectively in these cells. A 34% increase in cellular GSH level had no effect on the growth of HT-29 cells, nor on the cytotoxic activity of 5FU as determined by the MTT colorimetric assay and cell counts. A 50% reduction in the cellular GSH level was found to enhance 5FU cytotoxicity by 20% to 31% as determined by the MTT colorimetric assay, depending on the 5FU concentration. This study shows that a moderate change in the GSH level in HT-29 cells had little or no effect on the cells’ growth, but a decrease in cellular GSH level slightly enhanced the cytotoxic activity of 5FU in these cells.

Chinery, R., J. A. Brockman, et al. (1997). “Antioxidants enhance the cytotoxicity of chemotherapeutic agents in colorectal cancer: a p53-independent induction of p21WAF1/CIP1 via C/EBPbeta.” Nat Med 3(11): 1233-41.

Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States. Five-fluorouracil (5FU) remains the single most effective treatment for advanced disease, despite a response rate of only 20%. Herein, we show that the antioxidants pyrrolidinedithiocarbamate and vitamin E induce apoptosis in CRC cells. This effect is mediated by induction of p21WAF1/CIP1, a powerful inhibitor of the cell cycle, through a mechanism involving C/EBPbeta (a member of the CCAAT/enhancer binding protein family of transcription factors), independent of p53. Antioxidants significantly enhance CRC tumor growth inhibition by cytotoxic chemotherapy in vitro (5FU and doxorubicin) and in vivo (5FU). Thus, chemotherapeutic agents administered in the presence of antioxidants may provide a novel therapy for colorectal cancer.

Choo, M. K., H. Sakurai, et al. (2008). “A ginseng saponin metabolite suppresses tumor necrosis factor-alpha-promoted metastasis by suppressing nuclear factor-kappaB signaling in murine colon cancer cells.” Oncol Rep 19(3): 595-600.

SC-514, an inhibitor of IkappaB kinase beta (IKKbeta), blocked the TNF-alpha-induced activation of nuclear factor-kappaB (NF-kappaB) as well as the TNF-alpha-promoted metastasis of murine colon adenocarcinoma cells. We investigated the effect of 20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol (M1), a main intestinal bacterial metabolite of ginseng, on the NF-kappaB-dependent metastasis. M1 was effective in suppressing the TNF-alpha-induced activation of NF-kappaB, expression of matrix metalloprotease-9 (MMP-9), migration and invasion. The TNF-alpha-evoked increase in lung and liver metastasis of colon carcinoma was also abrogated by treatment with M1 in vitro. These results suggest that ginseng has potential to suppress inflammation-related metastasis by downregulating the NF-kappaB signaling pathway.

Conklin, K. A. (2000). “Dietary antioxidants during cancer chemotherapy: impact on chemotherapeutic effectiveness and development of side effects.” Nutr Cancer 37(1): 1-18.

Curtin, N. J. and A. N. Hughes (2001). “Pemetrexed disodium, a novel antifolate with multiple targets.” Lancet Oncol 2(5): 298-306.

Pemetrexed disodium is a potent new antifolate which inhibits many folate-dependent reactions that are essential for cell proliferation. Its primary target is thymidylate synthase but it also inhibits folate-dependent enzymes involved in purine synthesis. Cells that are resistant to antifolates are generally less resistant to pemetrexed, irrespective of the mechanism of resistance. Pemetrexed has shown good activity in preclinical models with human tumour cells and xenografts. In the majority of clinical trials of pemetrexed, the dose-limiting toxic effect is neutropenia; other side-effects are mostly gastrointestinal. Preclinical studies indicate that the toxic effects of pemetrexed can be reduced by dietary folate, resulting in an improved therapeutic index. Low folate status is also associated with higher levels of toxicity in patients. As a single agent pemetrexed has shown good activity against non-small-cell lung cancer, squamous-cell carcinoma of head and neck, colon cancer, and breast cancer, and it appears to be particularly active in combination with cisplatin against non-small-cell lung cancer and mesothelioma. Phase II and III studies are underway.

Daniele, B., F. Perrone, et al. (2001). “Oral glutamine in the prevention of fluorouracil induced intestinal toxicity: a double blind, placebo controlled, randomised trial.” Gut 48(1): 28-33.

BACKGROUND: 5-Fluorouracil (FU) in association with folinic acid (FA) is the most frequently used chemotherapeutic agent in colorectal cancer but it often causes diarrhoea. Animal and human studies suggest that glutamine stimulates intestinal mucosal growth. AIM: To determine if oral glutamine prevents changes in intestinal absorption (IA) and permeability (IP) induced by FU/FA. METHODS: Seventy chemotherapy naive patients with colorectal cancer were randomly assigned to oral glutamine (18 g/day) or placebo before the first cycle of FU (450 mg/m(2)) and FA (100 mg/m(2)) administered intravenously for five days. Treatment was continued for 15 days, starting five days before the beginning of chemotherapy. IA (D-xylose urinary excretion) and IP (cellobiose-mannitol test) were assessed at baseline and four and five days after the end of the first cycle of chemotherapy, respectively. Patients kept a daily record of diarrhoea, scored using the classification system of the National Cancer Institute (Bethesda, Maryland, USA). Duration of diarrhoea was recorded and the area under the curve (AUC) was calculated for each patient. RESULTS: Baseline patient characteristics and basal values of IP and IA tests were similar in the two arms. After one cycle of chemotherapy, the reduction in IA (D-xylose absorption) was more marked in the placebo arm (7.1% v 3. 8%; p=0.02); reduction of IP to mannitol was higher in the placebo arm (9.2% v 4.5%; p=0.02); and urinary recovery of cellobiose was not different between the study arms (p=0.60). Accordingly, the cellobiose-mannitol ratio increased more in the placebo arm (0.037 v 0.012; p=0.04). Average AUC of diarrhoea (1.9 v 4.5; p=0.09) and average number of loperamide tablets taken (0.4 v 2.6; p=0.002) were reduced in the glutamine arm. CONCLUSIONS: Glutamine reduces changes in IA and IP induced by FU and may have a protective effect on FU induced diarrhoea.

Doyle, L. A., D. D. Ross, et al. (1995). “An etoposide-resistant lung cancer subline overexpresses the multidrug resistance-associated protein.” Br J Cancer 72(3): 535-42.

Du, B., L. Jiang, et al. (2006). “Synergistic inhibitory effects of curcumin and 5-fluorouracil on the growth of the human colon cancer cell line HT-29.” Chemotherapy 52(1): 23-8.

The synergistic effect of combination treatment with COX-2 inhibitors and chemotherapy may be another promising therapy regimen in the future treatment of colorectal cancer. Curcumin, a major yellow pigment in turmeric which is used widely all over the world, inhibits the growth of human colon cancer cell line HT-29 significantly and specifically inhibits the expression of COX-2 protein. However, the worldwide exposure of populations to curcumin raised the question of whether this agent would enhance or inhibit the effects of chemotherapy. In this report, we evaluated the growth-inhibitory effect of curcumin and a traditional chemotherapy agent, 5-FU, against the proliferation of a human colon cancer cell line (HT-29). The combination effect was quantitatively determined using the method of median-effect principle and the combination index. The inhibition of COX-2 expression after treatment with the curcumin-5-FU combination was also evaluated by Western blot analysis. The IC(50) value in the HT-29 cells for curcumin was 15.9 +/- 1.96 microM and for 5-FU it was 17.3 +/- 1.85 microM. When curcumin and 5-FU were used concurrently, synergistic inhibition of growth was quantitatively demonstrated. The level of COX-2 protein expression was reduced almost 6-fold after the combination treatment. Our results demonstrate synergism between curcumin and 5-FU at higher doses against the human colon cancer cell line HT-29. This synergism was associated with the decreased expression of COX-2 protein.

Engel, D., A. Nudelman, et al. (2008). “Novel Prodrugs of Tegafur that Display Improved Anticancer Activity and Antiangiogenic Properties.” J Med Chem 51(2): 314-23.

New and more potent prodrugs of the 5-fluorouracyl family derived by hydroxymethylation or acyloxymethylation of 5-fluoro-1-(tetrahydro-2-furanyl)-2,4(1 H,3 H)-pyrimidinedione (tegafur, 1) are described. The anticancer activity of the butyroyloxymethyl-tegafur derivative 3 and not that of tegafur was attenuated by the antioxidant N-acetylcysteine, suggesting that the increased activity of the prodrug is in part mediated by an increase of reactive oxygen species. Compound 3 in an in vitro matrigel assay was found to be a more potent antiangiogenic agent than tegafur. In vivo 3 was significantly more potent than tegafur in inhibiting 4T1 breast carcinoma lung metastases and growth of HT-29 human colon carcinoma tumors in a mouse xenograft. In summary, the multifunctional prodrugs of tegafur display selectivity toward cancer cells, antiangiogenic activity, and anticancer activities in vitro and in vivo, superior to those of tegafur. 5-Fluoro-1-(tetrahydro-2-furanyl)-2,4(1 H,3 H)-pyrimidinedione (tegafur, 1), the oral prodrug of 5-FU, has been widely used for treatment of gastrointestinal malignancies with modest efficacy. The aim of this study was to develop and characterize new and more potent prodrugs of the 5-FU family derived by hydroxymethylation or acyloxymethylation of tegafur. Comparison between the effect of tegafur and the new prodrugs on the viability of a variety of cancer cell lines showed that the IC 50 and IC 90 values of the novel prodrugs were 5-10-fold lower than those of tegafur. While significant differences between the IC 50 values of tegafur were observed between the sensitive HT-29 and the resistant LS-1034 colon cancer cell lines, the prodrugs affected them to a similar degree, suggesting that they overcame drug resistance. The increased potency of the prodrugs could be attributed to the antiproliferative contribution imparted by formaldehyde and butyric acid, released upon metabolic degradation. The anticancer activity of the butyroyloxymethyl-tegafur derivative 3 and not that of tegafur was attenuated by the antioxidant N-acetylcysteine, suggesting that the increased activity of the prodrug is in part mediated by an increase of reactive oxygen species. Compound 3 in an in vitro matrigel assay was found to be a more potent antiangiogenic agent than tegafur. In vivo 3 was significantly more potent than tegafur in inhibiting 4T1 breast carcinoma lung metastases and growth of HT-29 human colon carcinoma tumors in a mouse xenograft. In summary, the multifunctional prodrugs of tegafur display selectivity toward cancer cells, antiangiogenic activity and anticancer activities in vitro and in vivo, superior to those of tegafur.

Fernandez-Luna, J. L. (2007). “Apoptosis regulators as targets for cancer therapy.” Clin Transl Oncol 9(9): 555-62.

Apoptosis serves to remove excess or damaged cells and its dysregulation may lead to a number of pathological disorders including cancer. Studies during the last 20 years have unravelled much of the molecular mechanisms that control apoptosis. Whether a cell dies in response to diverse apoptotic stimuli, including DNA-damaging agents, is determined largely by interactions between proteins of the Bcl-2 family. A death signal is transmitted through the BH3-only proteins to Bax and Bak which in turn permeabilise the outer mitochondrial membrane allowing the release of apoptogenic factors, which triggers activation of cell-deathpromoting caspases. These proteolytic enzymes are tightly controlled by members of the inhibitor of apoptosis (IAP) family. Activation of the caspase cascade via cell death receptors also represents a key apoptotic pathway in both normal and tumour cells. Basic knowledge of these apoptosis regulators provides the basis for novel therapeutic strategies aimed at promoting tumour cell death or enhancing susceptibility to apoptotic inducers. This review focuses on these strategies.

Fogt, F., A. Wellmann, et al. (2001). “Glut-1 expression in dysplastic and regenerative lesions of the colon.” Int J Mol Med 7(6): 615-9.

Monosaccaride transporter proteins are responsible for transmembrane transport of monosaccarides into cells. Glucose transporter protein 1 (Glut-1) is most prevalent in the cell membranes of erythrocytes and facilitates transport of glucose in tissues with barrier functions, i.e. blood brain barrier. Expression of Glut-1 in malignant tumors is increased due to increased metabolic need of the proliferating cell populations. In colorectal adenomas and carcinomas, membranous expression of Glut-1 has been associated with higher grade of tumors and decreased survival time. We studied the expression of Glut-1 in dysplastic proliferations of the colon which included sporadic adenomas and dysplasia associated lesions (DALM) in patients with ulcerative colitis and reactive/regenerative proliferations of the colon, including non-dysplastic chronic colitis, acute colitis and ischemia. Two patterns of Glut-1 expression were detected. Most adenomas and DALMs showed at least focal membranous expression of Glut-1. In addition a second staining pattern was recognized which consisted of prominent supranuclear dots. This pattern of staining was not only seen in adenomas and DALM but also in non-dysplastic areas immediately surrounding sporadic adenomas, in regenerative chronic colitis and in areas surrounding acute inflammation. Areas away from dysplasia did not show any positive staining for Glut-1. We conclude that two distinct patterns of Glut-1 expression may be found in colonic epithelial proliferation: membranous staining, associated with dysplasia, and, heretofore not described, supranuclear staining which may be related to Glut-1 expression secondary to expression of specific growth factors and not necessarily related to dysplasia.

Gamelin, L., M. Boisdron-Celle, et al. (2004). “Prevention of oxaliplatin-related neurotoxicity by calcium and magnesium infusions: a retrospective study of 161 patients receiving oxaliplatin combined with 5-Fluorouracil and leucovorin for advanced colorectal cancer.” Clin Cancer Res 10(12 Pt 1): 4055-61.

PURPOSE: Oxaliplatin is active in colorectal cancer. Sensory neurotoxicity is its dose-limiting toxicity. It may come from an effect on neuronal voltage-gated Na channels, via the liberation one its metabolite, oxalate. We decided to use Ca and Mg as oxalate chelators. EXPERIMENTAL DESIGN: A retrospective cohort of 161 patients treated with oxaliplatin + 5-fluorouracil and leucovorin for advanced colorectal cancer, with three regimens of oxaliplatin (85 mg/m(2)/2w, 100/2w, 130/3w) was identified. Ninety-six patients received infusions of Ca gluconate and Mg sulfate (1 g) before and after oxaliplatin (Ca/Mg group) and 65 did not. RESULTS: Only 4% of patients withdrew for neurotoxicity in the Ca/Mg group versus 31% in the control group (P = 0.000003). The tumor response rate was similar in both groups. The percentage of patients with grade 3 distal paresthesia was lower in Ca/Mg group (7 versus 26%, P = 0.001). Acute symptoms such as distal and lingual paresthesia were much less frequent and severe (P = 10(-7)), and pseudolaryngospasm was never reported in Ca/Mg group. At the end of the treatment, 20% of patients in Ca/Mg group had neuropathy versus 45% (P = 0.003). Patients with grade 2 and 3 at the end of the treatment in the 85 mg/m(2) oxaliplatin group recovered significantly more rapidly from neuropathy than patients without Ca/Mg. CONCLUSIONS: Ca/Mg infusions seem to reduce incidence and intensity of acute oxaliplatin-induced symptoms and might delay cumulative neuropathy, especially in 85 mg/m(2) oxaliplatin dosage.

Goto, S., K. Kamada, et al. (2002). “Significance of nuclear glutathione S-transferase pi in resistance to anti-cancer drugs.” Jpn J Cancer Res 93(9): 1047-56.

Recent study has shown that nuclear glutathione S-transferase (GST) pi accumulates in cancer cells resistant to doxorubicin hydrochloride (DOX) and may function to prevent nuclear DNA damage caused by DOX (Goto et al., FASEB J., 15, 2702 – 2714 (2001)). It is not clear if the amount of nuclear GSTpi increases in response to other anti-cancer drugs and if so, what is the physiological significance of the nuclear transfer of GSTpi in the acquisition of drug-resistance in cancer cells. In the present study, we employed three cancer cell lines, HCT8 human colonic cancer cells, A549 human lung adenocarcinoma cells, and T98G human glioblastoma cells. We estimated the nuclear transfer of GSTpi induced by the anti-cancer drugs cisplatin (CDDP), irinotecan hydrochloride (CPT-11), etoposide (VP-16) and 5-fluorouracil (5-FU). It was found that: (1) Nuclear GSTpi accumulated in these cancer cells in response to CDDP, DOX, CPT-11, VP-16 and 5-FU. (2) An inhibitor of the nuclear transport of GSTpi, edible mushroom lectin (Agaricus bisporus lectin, ABL), increased the sensitivity of the cancer cells to DOX and CDDP, and partially to CPT-11. Treatment with ABL had no apparent effect on the cytotoxicity of VP-16 and 5-FU. These results suggest that inhibitors of the nuclear transfer of GSTpi have practical value in producing an increase of sensitivity to DOX, CDDP and CPT-11.

Grubben, M. J., F. M. Nagengast, et al. (2001). “The glutathione biotransformation system and colorectal cancer risk in humans.” Scand J Gastroenterol Suppl(234): 68-76.

Evidence for a protective role of the glutathione biotransformation system in carcinogenesis is growing. However, most data on this system in relation to colorectal cancer originate from animal studies. Here we review the human data. In humans, a significant association was found between glutathione S-transferase (GST) activity in the mucosa along the gastrointestinal tract and the corresponding tumour incidence. Low activity was correlated with high tumour incidence and vice versa. Also, in normal colonic mucosa, GST activity is lower in patients at risk of colon cancer than in healthy controls and therefore interventions which increase the glutathione detoxification capacity may reduce cancer incidence. Consumption of vegetables and fruit is associated with a lower risk of colorectal cancer. Human intervention studies showed that (components from) vegetables induced colonic glutathione detoxification capacity. Such an effect could contribute to a lower colon cancer risk, but further data are needed. The human GSTs consist of four main classes–alpha (A), mu (M), pi (P) and theta (T)–each of which is divided into one or more isoforms. Functional polymorphisms are known for the GST genes M1, P1 and T1 and they all lead to less active enzymes compared to the wild-type gene products. However, studies that compared these GST polymorphisms in relation to colon cancer risk were not conclusive with respect to an increased or decreased risk of a particular genotype. Diet or medication can also influence the expression levels of specific isoenzymes and the effect of such interventions on cancer risk deserves more attention.

Hatcher, H., R. Planalp, et al. (2008). “Curcumin: From ancient medicine to current clinical trials.” Cell Mol Life Sci.

Curcumin is the active ingredient in the traditional herbal remedy and dietary spice turmeric (Curcuma longa). Curcumin has a surprisingly wide range of beneficial properties, including anti-inflammatory, antioxidant, chemopreventive and chemotherapeutic activity. The pleiotropic activities of curcumin derive from its complex chemistry as well as its ability to influence multiple signaling pathways, including survival pathways such as those regulated by NF-kappaB, Akt, and growth factors; cytoprotective pathways dependent on Nrf2; and metastatic and angiogenic pathways. Curcumin is a free radical scavenger and hydrogen donor, and exhibits both pro- and antioxidant activity. It also binds metals, particularly iron and copper, and can function as an iron chelator. Curcumin is remarkably non-toxic and exhibits limited bioavailability. Curcumin exhibits great promise as a therapeutic agent, and is currently in human clinical trials for a variety of conditions, including multiple myeloma, pancreatic cancer, myelodysplastic syndromes, colon cancer, psoriasis and Alzheimer’s disease.

Hidvegi, M., E. Raso, et al. (1999). “MSC, a new benzoquinone-containing natural product with antimetastatic effect.” Cancer Biother Radiopharm 14(4): 277-89.

An orally applicable fermentation product of wheat germ containing 0.04% substituted benzoquinone (MSC) has been invented by Hungarian chemists under the trade name of AVEMAR. Oral administration (3 g/kg body weight) of MSC enhances blastic transformation of splenic lymphocytes in mice. The same treatment shortens the survival time of skin grafts in a co-isogenic mouse skin transplantation model, pointing to the immune-reconstructive effect of MSC. A highly significant antimetastatic effect of MSC has been observed in three metastasis models (3LL-HH, B16, HCR-25). The antimetastatic effect of MSC–besides the immune-reconstitution–may also be due to its cell adhesion inhibitory, cell proliferation inhibitory, apoptosis enhancing, and antioxidant characteristics, also observed in our in vitro experiments. It is even more noteworthy that combined treatment with MSC and one of the following antineoplastic agents (5-FU and DTIC)–both in wide use in every day clinical practice–exhibited a significantly enhanced antimetastatic effect in appropriate metastasis models (established from C38 mouse colon carcinoma and B16 mouse melanoma respectively) as compared to the effect elicited by any component of these therapeutic compositions (MSC + 5-FU and MSC + DTIC) administered alone. The results show that the fermented wheat germ extract (MSC) has more than an additive effect and synergistically enhanced the metastasis inhibitory effect of both antineoplastic agents studied till now. It is also worthy of mention that the synchronous treatment with MSC profoundly decreased the toxic side effects of the applied antineoplastic agents (decreased weight loss etc). Based on the biological effects of MSC–shown to be non-toxic by subacute toxicology studies–this product may be used as an adjuvant in the therapy of malignant neoplasia and other diseases caused by or following immune-deficiency.

Hwang, J. T., J. Ha, et al. (2007). “Apoptotic effect of EGCG in HT-29 colon cancer cells via AMPK signal pathway.” Cancer Lett 247(1): 115-21.

EGCG [(-)epigallocatechin-3-gallate], a green tea-derived polyphenol, has been shown to suppress cancer cell proliferation, and interfere with the several signaling pathways and induce apoptosis. Practically, there is emerging evidence that EGCG has a potential to increase the efficacy of chemotherapy in patients. We hypothesized that EGCG may exert cell cytotoxicity through modulating AMPK (AMP-activated protein kinase) followed by the decrease in COX-2 expression. EGCG treatment to colon cancer cells resulted in a strong activation of AMPK and an inhibition of COX-2 expression. The decreased COX-2 expression as well as prostaglandin E(2) secretion by EGCG was completely abolished by inhibiting AMPK by an AMPK inhibitor, Compound C. Also, the activation of AMPK was accompanied with the reduction of VEGF (vascular endothelial growth factor) and glucose transporter, Glut-1 in EGCG-treated cancer cells. These findings support the regulatory role of AMPK in COX-2 expression in EGCG-treated cancer cells. Furthermore, we have found that reactive oxygen species (ROS) is an upstream signal of AMPK, and the combined treatment of EGCG and chemotherapeutic agents, 5-FU or Etoposide, exert a novel therapeutic effect on chemo-resistant colon cancer cells. AMPK, a molecule of newly defined cancer target, was shown to control COX-2 in EGCG-treated colon cancer cells.

Hwang, J. T., J. Ha, et al. (2005). “Combination of 5-fluorouracil and genistein induces apoptosis synergistically in chemo-resistant cancer cells through the modulation of AMPK and COX-2 signaling pathways.” Biochem Biophys Res Commun 332(2): 433-40.

5-Fluorouracil (5-FU) is one of the widely used chemotherapeutic drugs targeting various cancers, but its chemo-resistance remains as a major obstacle in clinical settings. In the present study, HT-29 colon cancer cells were markedly sensitized to apoptosis by both 5-FU and genistein compared to the 5-FU treatment alone. There is an emerging evidence that genistein, soy-derived phytoestrogen, may have potential as a chemotherapeutic agent capable of inducing apoptosis or suppressing tumor promoting proteins such as cyclooxygenase-2 (COX-2). However, the precise mechanism of cellular cytotoxicity of genistein is not known. The present study focused on the correlation of AMPK and COX-2 in combined cytotoxicity of 5-FU and genistein, since AMPK is known as a primary cellular homeostasis regulator and a possible target molecule of cancer treatment, and COX-2 as cell proliferation and anti-apoptotic molecule. Our results demonstrated that the combination of 5-FU and genistein abolished the up-regulated state of COX-2 and prostaglandin secretion caused by 5-FU treatment in HT-29 colon cancer cells. These appear to be followed by the specific activation of AMPK and the up-regulation of p53, p21, and Bax by genistein. Under same conditions, the induction of Glut-1 by 5-FU was diminished by the combination treatment with 5-FU and genistein. Furthermore, the reactive oxygen species (ROS) was found as an upstream signal for AMPK activation by genistein. These results suggested that the combination of 5-FU and genistein exert a novel chemotherapeutic effect in colon cancers, and AMPK may be a novel regulatory molecule of COX-2 expression, further implying its involvement in cytotoxicity caused by genistein.

Hwang, J. T., Y. M. Kim, et al. (2006). “Selenium regulates cyclooxygenase-2 and extracellular signal-regulated kinase signaling pathways by activating AMP-activated protein kinase in colon cancer cells.” Cancer Res 66(20): 10057-63.

Epidemiologic and experimental evidences indicate that selenium, an essential trace element, can reduce the risk of a variety of cancers. Protection against certain types of cancers, particularly colorectal cancers, is closely associated with pathways involving cyclooxygenase-2 (COX-2). We found that AMP-activated protein kinase (AMPK), which functions as a cellular energy sensor, mediates critical anticancer effects of selenium via a COX-2/prostaglandin E(2) signaling pathway. Selenium activated AMPK in tumor xenografts as well as in colon cancer cell lines, and this activation seemed to be essential to the decrease in COX-2 expressions. Transduction with dominant-negative AMPK into colon cancer cells or application of cox-2(-/-)-negative cells supported the evidence that AMPK is an upstream signal of COX-2 and inhibits cell proliferation. In HT-29 colon cancer cells, carcinogenic agent 12-O-tetradecanoylphorbol-13-acetate (TPA) activated extracellular signal-regulated kinase (ERK) that led to COX-2 expression and selenium blocked the TPA-induced ERK and COX-2 activation via AMPK. We also showed the role of a reactive oxygen species as an AMPK activation signal in selenium-treated cells. We propose that AMPK is a novel and critical regulatory component in selenium-induced cancer cell death, further implying AMPK as a prime target of tumorigenesis.

Ichikawa, D., T. Takahashi, et al. (1998). “[Postoperative management of the preserved rectal segment in patients with familial polyposis: the use of 5-fluorouracil suppositories and green tea extract to inhibit tumor growth].” Nippon Geka Gakkai Zasshi 99(6): 391-5.

We report the clinical details of seven patients with familial polyposis. They underwent subtotal colectomy with ileorectostomy, and were treated with 5-fluorouracil suppositories and green tea extract after surgery. Some regression of the polyps in the preserved rectal segment was observed, and no rectal cancer developed in any of these patients.

Jaiswal, A. S., B. P. Marlow, et al. (2002). “Beta-catenin-mediated transactivation and cell-cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells.” Oncogene 21(55): 8414-27.

The development of nontoxic natural agents with chemopreventive activity against colon cancer is the focus of investigation in many laboratories. Curcumin (feruylmethane), a natural plant product, possesses such chemopreventive activity, but the mechanisms by which it prevents cancer growth are not well understood. In the present study, we examined the mechanisms by which curcumin treatment affects the growth of colon cancer cells in vitro. Results showed that curcumin treatment causes p53- and p21-independent G(2)/M phase arrest and apoptosis in HCT-116(p53(+/+)), HCT-116(p53(-/-)) and HCT-116(p21(-/-)) cell lines. We further investigated the association of the beta-catenin-mediated c-Myc expression and the cell-cell adhesion pathways in curcumin-induced G(2)/M arrest and apoptosis in HCT-116 cells. Results described a caspase-3-mediated cleavage of beta-catenin, decreased transactivation of beta-catenin/Tcf-Lef, decreased promoter DNA binding activity of the beta-catenin/Tcf-Lef complex, and decreased levels of c-Myc protein. These activities were linked with decreased Cdc2/cyclin B1 kinase activity, a function of the G(2)/M phase arrest. The decreased transactivation of beta-catenin in curcumin-treated HCT-116 cells was unpreventable by caspase-3 inhibitor Z-DEVD-fmk, even though the curcumin-induced cleavage of beta-catenin was blocked in Z-DEVD-fmk pretreated cells. The curcumin treatment also induced caspase-3-mediated degradation of cell-cell adhesion proteins beta-catenin, E-cadherin and APC, which were linked with apoptosis, and this degradation was prevented with the caspase-3 inhibitor. Our results suggest that curcumin treatment impairs both Wnt signaling and cell-cell adhesion pathways, resulting in G(2)/M phase arrest and apoptosis in HCT-116 cells.

Jordan, A. and J. Stein (2003). “Effect of an omega-3 fatty acid containing lipid emulsion alone and in combination with 5-fluorouracil (5-FU) on growth of the colon cancer cell line Caco-2.” Eur J Nutr 42(6): 324-31.

BACKGROUND: In this study we examined the effects of a fish oil-based lipid emulsion (FO) rich in omega-3 fatty acids, which is used in humans as a component of parenteral nutrition, on the growth of the colon cancer cell line Caco-2. AIM OF THE STUDY: The aim of the present study was to investigate whether the FO influences growth and chemosensitivity of the colon cancer cell line Caco-2. FO was tested alone and in combination with the anticancer drug 5-fluorouracil (5-FU). METHODS: Cell numbers were determined with crystal violet staining, cell cycle distribution was assessed using a flow cytometer and apoptosis was visualized by staining nuclei with diamino-phenylindole hydrochloride. RESULTS: FO inhibited growth of Caco-2 cells in a time and dose dependent manner. FO treatment evoked apoptosis as confirmed by cell morphology. Cell cycle analysis identified an accumulation of cells in the G(2)/M phase after incubation with FO. The combined treatment of the cells with FO and 5-FU resulted in a significant enhancement of the growth inhibition seen after exposure to either substance alone. Treatment of the cells with 5-FU specifically blocked the cell cycle in the S phase. The combined treatment of 5-FU with FO showed a further increase in the accumulation of cells in the S phase. CONCLUSIONS: In conclusion, FO has a potent antiproliferative effect on Caco-2 cells, at least in part, due to a decrease in the progression of the cell cycle and the induction of apoptosis. The combination of FO with 5-FU results in an additive growth inhibitory effect.

Katoh, R. and M. Ooshiro (2007). “Enhancement of antitumor effect of tegafur/uracil (UFT) plus leucovorin by combined treatment with protein-bound polysaccharide, PSK, in mouse models.” Cell Mol Immunol 4(4): 295-9.

We evaluated the antitumor effect of combined therapy with tegafur/uracil (UFT) plus leucovorin (LV) (UFT/LV) and protein-bound polysaccharide, PSK, in three mouse models of transplantable tumors. UFT/LV showed antitumor effect against Meth A sarcoma, and the antitumor effect was enhanced when PSK given concomitantly. UFT/LV showed antitumor effect to Lewis lung carcinoma and PSK alone also showed antitumor effect at high dose, but a combination of UFT/LV and PSK resulted in no enhanced antitumor effect. Colon 26 carcinoma was weakly responsive to UFT/LV, and no enhancement of antitumor effect was found even PSK was used in combination. In conclusion, while the effect of PSK varies depending on tumor, combined use of UFT/LV and PSK may be expected to augment the antitumor effect.

Kim, K. H., H. Y. Park, et al. (2005). “[The inhibitory effect of curcumin on the growth of human colon cancer cells (HT-29, WiDr) in vitro].” Korean J Gastroenterol 45(4): 277-84.

BACKGROUND/AIMS: The effects of curcumin on the growth of human colon cancer cell lines, HT-29 and WiDr cells were examined and the effects of 5-fluorouracil (5-FU) were also studied. METHODS: The growth of HT-29 and WiDr cells were examined by counting cell number on two and four days treatment with 1-40 microm of curcumin, and 0.1 microg/mL, 0.3 microg/mL of 5-FU. The reversibility of curcumin was examined on one day to seven days treatment with 10 microm curcumin after seeding to 2 x 10(4) cells/well. To examine the inhibitory effects of curcumin, cell cycle analysis was done on the HT-29 cells after four days treatment with 20 microm curcumin. RESULTS: Curcumin inhibited the growth of HT-29 and WiDr cells in a dose-dependent fashion. The growth rate of the group in which curcumin was removed by media change 24 hours after the treatment of curcumin was not different from that of control group. Curcumin combined with 5-FU markedly inhibited the growth of HT-29 and WiDr cells compared to curcumin or 5-FU alone. After four days treatment of HT-29 cells with 20 microm curcumin, the fraction of cells in G2-M phase was 35.3% in curcumin group, much higher than 13.8% of the control group. CONCLUSIONS: Curcumin significantly inhibited the growth of HT-29 and WiDr cells in a dose-dependent, reversible fashion.

Kim, Y. M., J. T. Hwang, et al. (2007). “Involvement of AMPK signaling cascade in capsaicin-induced apoptosis of HT-29 colon cancer cells.” Ann N Y Acad Sci 1095: 496-503.

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is activated during ATP-depleting metabolic states, such as hypoxia, heat shock, oxidative stress, and exercise. As a highly conserved heterotrimeric kinase that functions as a major metabolic switch to maintain energy homeostasis, AMPK has been shown to exert as an intrinsic regulator of mammalian cell cycle. Moreover, AMPK cascade has emerged as an important pathway implicated in cancer control. In this article, we have investigated the effects of capsaicin on apoptosis in relation to AMPK activation in colon cancer cell. Capsaicin-induced apoptosis was revealed by the presence of nucleobodies in the capsaicin-treated HT-29 colon cancer cells. Concomitantly, the activation of AMPK and the increased expression of the inactive form of acetyl-CoA carboxylase (ACC) were detected in capsaicin-treated colon cancer cells. We showed that both capsaicin and 5′-aminoimidazole-4-carboxamide-1-beta-D-ribonucleoside (AICAR), an AMPK activator possess the AMPK-activating capacity as well as apoptosis-inducing properties. Evidence of the association between AMPK activation and the increased apoptosis in HT-29 colon cancer cells by capsaicin treatment, and further findings of the correlation of the activated AMPK and the elevated apoptosis by cotreatment of AICAR and capsaicin support AMPK as an important component of apoptosis, as well as a possible target of cancer control.

Kitajima, M., Y. Ikeda, et al. (1987). “[The effect of tegafur suppository and glutathione in patients with gastric and colonic cancer with special reference to the histopathological anticancer effect].” Gan To Kagaku Ryoho 14(11): 3131-9.

The purpose of these studies is to evaluate the anticancerous effects of tegafur suppository and Glutathione (GSH) as enhanced drug and compare the difference of the histopathological effects and tissue concentration of 5-FU and FT-207 in gastric and colon cancer. Thirty three patients with gastric cancer and 17 with colon cancer were treated by tegafur suppository at a dose of 1,500 mg/day and GSH, 1,200 mg/day intravenously. These patients were clinically divided into two groups, one of which was treated with tegafur suppository (Group A) and another administered with suppository and GSH (Group B). Five-fluorouracil was measured by GC-MF method and FT-207 was also done by HPLC method. After surgery, relationship between tissue concentration of 5-FU and histopathological effects were investigated. In gastric cancer, 5-FU concentration in cancer tissue was significantly kept high level in cancer tissue in patients treated with tegafur and GSH (Group B). However, there was no same results in colon cancer. These results seemed to be the difference of organ specificity. According to histopathological studies, well differentiated adenocarcinoma including papillary carcinoma were markedly effective compared to poorly differentiated adenocarcinoma in both cancer. This difference of anticancerous effect was supposed to be microangiographically different of microvascular architecture and quantity of anticancerous agents in tumor.

Kokura, S., N. Yoshida, et al. (2005). “The radical scavenger edaravone enhances the anti-tumor effects of CPT-11 in murine colon cancer by increasing apoptosis via inhibition of NF-kappaB.” Cancer Lett 229(2): 223-33.

The transcription factor NF-kappaB is reportedly activated by anti-cancer chemotherapeutic compounds in many cancer cell lines and NF-kappaB activation is one mechanism by which tumors become resistant to apoptosis. Antioxidants have been reported to serve as potent NF-kB inhibitors. In this study, we investigated the ability of edaravone to enhance apoptosis induced by CPT-11 through inhibition of NF-kB. In vitro, SN38, the active metabolite of CPT-11, induced activation of NF-kB, the production of intracellular reactive oxygen species, the activation of caspase-3, and apoptosis in colon26 cells. Pretreatment with edaravone scavenged the SN38-produced reactive oxygen species, and inhibited the SN38-induced activation of NF-kB. Moreover, edaravone enhanced the activation of caspase-3, and the level of apoptosis induced by SN38. In vivo, the combination of edaravone with CPT-11 reduced subcutaneous tumor growth and number of pulmonary metastases more effectively than CPT-11 alone. These results demonstrate that the combination of edaravone with CPT-11 may constitute a new strategy for treating primary and metastatic colon cancer.

Kurokawa, H., K. Nishio, et al. (1997). “Effect of glutathione depletion on cisplatin resistance in cancer cells transfected with the gamma-glutamylcysteine synthetase gene.” Jpn J Cancer Res 88(2): 108-10.

Lee, C. H., Y. T. Jeon, et al. (2007). “NF-kappaB as a potential molecular target for cancer therapy.” Biofactors 29(1): 19-35.

Nuclear factor kappaB (NF-kappaB), a transcription factor, plays an important role in carcinogenesis as well as in the regulation of immune and inflammatory responses. NF-kappaB induces the expression of diverse target genes that promote cell proliferation, regulate apoptosis, facilitate angiogenesis and stimulate invasion and metastasis. Furthermore, many cancer cells show aberrant or constitutive NF-kappaB activation which mediates resistance to chemo- and radio-therapy. Therefore, the inhibition of NF-kappaB activation and its signaling pathway offers a potential cancer therapy strategy. In addition, recent studies have shown that NF-kappaB can also play a tumor suppressor role in certain settings. In this review, we focus on the role of NF-kappaB in carcinogenesis and the therapeutic potential of targeting NF-kappaB in cancer therapy.

Lee, C. S., S. Y. Park, et al. (2004). “Effect of change in cellular GSH levels on mitochondrial damage and cell viability loss due to mitomycin c in small cell lung cancer cells.” Biochem Pharmacol 68(9): 1857-67.

Luo, Z., A. K. Saha, et al. (2005). “AMPK, the metabolic syndrome and cancer.” Trends Pharmacol Sci 26(2): 69-76.

The fuel-sensing enzyme 5′-AMP-activated protein kinase (AMPK) has a major role in the regulation of cellular lipid and protein metabolism in response to stimuli such as exercise, changes in fuel availability and the adipocyte-derived hormones leptin and adiponectin. Recent studies indicate that abnormalities in cellular lipid metabolism are involved in the pathogenesis of the metabolic syndrome, possibly because of dysregulation of AMPK and malonyl-CoA, a closely related molecule. As we discuss in this article, several findings also point to a link between AMPK and the growth and/or survival of some cancer cells. Thus, it has been demonstrated recently that the tumor suppressor LKB1 is a kinase that has a major role in phosphorylating and activating AMPK, and that another tumor suppressor, tuberous sclerosis complex 2, is phosphorylated and activated by AMPK. In addition, other studies indicate that mammalian homolog of target of rapamycin (mTOR), which has been implicated in the pathogenesis of insulin resistance and many types of cancer, is inhibited by AMPK.

Maddika, S., S. R. Ande, et al. (2007). “Cell survival, cell death and cell cycle pathways are interconnected: implications for cancer therapy.” Drug Resist Updat 10(1-2): 13-29.

The partial cross-utilization of molecules and pathways involved in opposing processes like cell survival, proliferation and cell death, assures that mutations within one signaling cascade will also affect the other opposite process at least to some extent, thus contributing to homeostatic regulatory circuits. This review highlights some of the connections between opposite-acting pathways. Thus, we discuss the role of cyclins in the apoptotic process, and in the regulation of cell proliferation. CDKs and their inhibitors like the INK4-family (p16(Ink4a), p15(Ink4b), p18(Ink4c), p19(Ink4d)), and the Cip1/Waf1/Kip1-2-family (p21(Cip1/Waf1), p27(Kip1), p57(Kip2)) are shown both in the context of proliferation regulators and as contributors to the apoptotic machinery. Bcl2-family members (i.e. Bcl2, Bcl-X(L) Mcl-1(L); Bax, Bok/Mtd, Bak, and Bcl-X(S); Bad, Bid, Bim(EL), Bmf, Mcl-1(S)) are highlighted both for their apoptosis-regulating capacity and also for their effect on the cell cycle progression. The PI3-K/Akt cell survival pathway is shown as regulator of cell metabolism and cell survival, but examples are also provided where aberrant activity of the pathway may contribute to the induction of apoptosis. Myc/Mad/Max proteins are shown both as a powerful S-phase driving complex and as apoptosis-sensitizers. We also discuss multifunctional proteins like p53 and Rb (RBL1/p107, RBL2/p130) both in the context of G1-S transition and as apoptotic triggers. Finally, we reflect on novel therapeutic approaches that would involve redirecting over-active survival and proliferation pathways towards induction of apoptosis in cancer cells.

Mamiya, N., T. Kono, et al. (2007). “[A case of neurotoxicity reduced with goshajinkigan in modified FOLFOX6 chemotherapy for advanced colon cancer].” Gan To Kagaku Ryoho 34(8): 1295-7.

In performing FOLFOX (infusional 5-FU/LV with oxaliplatin) for advanced colorectal cancer, neurotoxicity of oxaliplatin (L-OHP) is the serious dose limiting factor. On the other hand, goshajinkigan is recently considered as an effective agent for the neurotoxicity of taxanes in Japan.We have applied goshajinkigan (TJ 107) for a case of advanced colon cancer with mFOLFOX 6, and experienced a reduction in numbness, the adverse effect of LOHP. A 57-year-old woman with descending colon cancer (H 1, P 3, Stage IV) underwent hemicolectomy D 2, rt.colectomy, bilateral oophorectomy, cholecystectomy and transverse colonostomy. After operation, mFOLFOX 6 was applied. In order to reduce the neurotoxicity of L-OHP, TJ 107 was used together from the third course. The severities of neurotoxicity before and after administration of TJ 107 were grade 2 and 1,respectively. TJ 107 could reduce or prevent the neurotoxicity of L-OHP.

Mans, D. R., G. J. Schuurhuis, et al. (1992). “Modulation by D,L-buthionine-S,R-sulphoximine of etoposide cytotoxicity on human non-small cell lung, ovarian and breast carcinoma cell lines.” Eur J Cancer 28A(8-9): 1447-52.

Meijer, C., N. H. Mulder, et al. (1990). “The role of glutathione in resistance to cisplatin in a human small cell lung cancer cell line.” Br J Cancer 62(1): 72-7.

Nadal, J. C., C. J. van Groeningen, et al. (1989). “Schedule-dependency of in vivo modulation of 5-fluorouracil by leucovorin and uridine in murine colon carcinoma.” Invest New Drugs 7(2-3): 163-72.

The effect of leucovorin (LV) given in various doses and schedules on the in vivo antitumor activity and toxicity of 5-fluorouracil (5FU) was studied in two murine colon cancer lines, i.e., Colon 26 (relatively resistant to 5FU) and Colon 38 (5FU sensitive), maintained in Balb-c and C57B1/6 mice, respectively. Mice were treated weekly with 5FU at the maximum tolerated dose, alone and in combination with LV. In Colon 26, neither simultaneous administration of 5FU and LV nor 5FU combined with delayed administration of LV potentiated the antitumor activity of 5FU. LV given twice – 1 hr before (50 mg/kg) and then together (50 mg/kg) with 5FU (100 mg/kg) – gave significantly better delay of tumor growth of both tumor lines than 5FU did alone (100 mg/kg). No differences were found after a total LV dose of 100 or 200 mg/kg. Delayed administration of uridine (3500 mg/kg) allowed the use of higher 5FU doses, which improved the antitumor effect on Colon 26. Systemic toxicity led to moderate weight loss in treated mice, but was comparable for mice treated with 5FU alone or combined with LV. Hematological toxicity consisted of moderate leukopenia (nadir 40%), which was observed with the most active schedule and was less severe than with 5FU alone. This schedule did not cause thrombocytopenia, but after discontinuation the thrombocyte count showed an overshoot. Addition of uridine to this schedule reduced hematological toxicity only slightly. It is concluded that LV potentiated the antitumor activity of 5FU against two solid tumor lines, i.e., a relatively resistant and a sensitive murine colon carcinoma, and that toxicity was moderate.

Nakagawa, Y., M. Iinuma, et al. (2007). “Characterized mechanism of alpha-mangostin-induced cell death: caspase-independent apoptosis with release of endonuclease-G from mitochondria and increased miR-143 expression in human colorectal cancer DLD-1 cells.” Bioorg Med Chem 15(16): 5620-8.

alpha-Mangostin, a xanthone from the pericarps of mangosteen (Garcinia mangostana Linn.), was evaluated for in vitro cytotoxicity against human colon cancer DLD-1 cells. The number of viable cells was consistently decreased by the treatment with alpha-mangostin at more than 20 microM. The cytotoxic effect of 20 microM alpha-mangostin was found to be mainly due to apoptosis, as indicated by morphological findings. Western blotting, the results of an apoptosis inhibition assay using caspase inhibitors, and the examination of caspase activity did not demonstrate the activation of any of the caspases tested. However, endonuclease-G released from mitochondria with the decreased mitochondrial membrane potential was shown. The levels of phospho-Erk1/2 were increased in the early phase until 1h after the start of treatment and thereafter decreased, and increased again in the late phase. On the other hand, the level of phospho-Akt was sharply reduced with the process of apoptosis after 6h of treatment. Interestingly, the level of microRNA-143, which negatively regulates Erk5 at translation, gradually increased until 24h following the start of treatment. We also examined the synergistic growth suppression in DLD-1 cells by the combined treatment of the cells with alpha-mangostin and 5-FU which is one of the most effective chemotherapeutic agents for colorectal adenocarcinoma. The co-treatment with alpha-mangostin and 5-FU, both at 2.5 microM, augmented growth inhibition compared with the treatment with 5 microM of alpha-mangostin or 5 microM 5-FU alone. These findings indicate unique mechanisms of alpha-mangostin-induced apoptosis and its action as an effective chemosensitizer.

Pai, R., T. Nakamura, et al. (2003). “Prostaglandins promote colon cancer cell invasion; signaling by cross-talk between two distinct growth factor receptors.” Faseb J 17(12): 1640-7.

Colorectal cancer is the second most frequent cancer in the Western world, often lethal when invasion and/or metastasis occur. In addition to hepatocyte growth factor (HGF), colon cancer invasion may be driven by prostaglandins, especially the E2 series (PGE2), generated by the cyclooxygenase-2 (Cox-2) enzyme. While concentration of PGE2 as well as expression of Cox-2, HGF receptor (c-Met-R), epidermal growth factor receptor (EGFR), and beta-catenin are all dramatically increased in colon cancers and implicated in their growth and invasion, the precise role of PGE2 in the latter process remains unclear. Here we provide evidence that PGE2 transactivates c-Met-R (contingent upon functional EGFR), increases tyrosine phosphorylation and nuclear accumulation of beta-catenin, and induces urokinase-type plasminogen activator receptor (uPAR) mRNA expression. This is accompanied by increased beta-catenin association with c-Met-R and enhanced colon cancer cell invasiveness. Inactivation of EGFR and c-Met-R significantly reduced PGE2-induced cancer cell invasiveness. Clinical relevance of these findings is confirmed by our immunohistochemical studies demonstrating that cancer cells in the invasive front overexpress Cox-2, c-Met-R, and beta-catenin. Our findings explain a functional relationship between prostaglandins, EGFR, and c-Met-R in colon cancer growth and invasion.

Patel, B. B., R. Sengupta, et al. (2008). “Curcumin enhances the effects of 5-fluorouracil and oxaliplatin in mediating growth inhibition of colon cancer cells by modulating EGFR and IGF-1R.” Int J Cancer 122(2): 267-73.

Curcumin (diferuloylmethane), which has been shown to inhibit growth of transformed cells, has no discernible toxicity and achieves high levels in colonic mucosa. 5-fluorouracil (5-FU) or 5-FU plus oxaliplatin (FOLFOX) remains the backbone of colorectal cancer chemotherapeutics, but with limited success. The present investigation was, therefore, undertaken to examine whether curcumin in combination with conventional chemotherapeutic agent(s)/regimen will be a superior therapeutic strategy for colorectal cancer. Indeed, results of our in vitro studies demonstrated that curcumin together with FOLFOX produced a significantly greater inhibition (p < 0.01) of growth and stimulated apoptosis (p < 0.001) of colon cancer HCT-116 and HT-29 cells than that caused by curcumin, 5-FU, curcumin + 5-FU or FOLFOX. These changes were associated with decreased expression and activation (tyrosine phosphorylation) of EGFR, HER-2, HER-3 (72-100%) and IGF-1R (67%) as well as their downstream effectors such as Akt and cycloxygenase-2 (51-97%). Furthermore, while these agents produced a 2-3-fold increase in the expression of IGF-binding protein-3 (IGFBP-3), curcumin together with FOLFOX caused a 5-fold increase in the same, when compared to controls. This in turn led to increased sequestration of IGF by IGFBP-3 rendering IGF-1 unavailable for binding to and activation of IGF-1R. We conclude that the superior effects of the combination therapy of curcumin and FOLFOX are due to attenuation of EGFRs and IGF-1R signaling pathways. We also suggest that inclusion of curcumin to the conventional chemotherapeutic agent(s)/regimen could be an effective therapeutic strategy for colorectal cancer.

Perumal, S. S., P. Shanthi, et al. (2005). “Augmented efficacy of tamoxifen in rat breast tumorigenesis when gavaged along with riboflavin, niacin, and CoQ10: effects on lipid peroxidation and antioxidants in mitochondria.” Chem Biol Interact 152(1): 49-58.

Porter, A. G. and R. U. Janicke (1999). “Emerging roles of caspase-3 in apoptosis.” Cell Death Differ 6(2): 99-104.

Caspases are crucial mediators of programmed cell death (apoptosis). Among them, caspase-3 is a frequently activated death protease, catalyzing the specific cleavage of many key cellular proteins. However, the specific requirements of this (or any other) caspase in apoptosis have remained largely unknown until now. Pathways to caspase-3 activation have been identified that are either dependent on or independent of mitochondrial cytochrome c release and caspase-9 function. Caspase-3 is essential for normal brain development and is important or essential in other apoptotic scenarios in a remarkable tissue-, cell type- or death stimulus-specific manner. Caspase-3 is also required for some typical hallmarks of apoptosis, and is indispensable for apoptotic chromatin condensation and DNA fragmentation in all cell types examined. Thus, caspase-3 is essential for certain processes associated with the dismantling of the cell and the formation of apoptotic bodies, but it may also function before or at the stage when commitment to loss of cell viability is made.

Press, M. F. and H. J. Lenz (2007). “EGFR, HER2 and VEGF pathways: validated targets for cancer treatment.” Drugs 67(14): 2045-75.

Targeted therapies are rationally designed to interfere with specific molecular events that are important in tumour growth, progression or survival. Several targeted therapies with anti-tumour activity in human cancer cell lines and xenograft models have now been shown to produce objective responses, delay disease progression and, in some cases, improve survival of patients with advanced malignancies. These targeted therapies include cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody; gefitinib and erlotinib, EGFR-specific tyrosine kinase inhibitors; trastuzumab, an anti-human EGFR type 2 (HER2)-related monoclonal antibody; lapatinib, a dual inhibitor of both EGFR- and HER2-associated tyrosine kinases; and bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody.On the basis of preclinical and clinical evidence, EGFR, HER2 and VEGF represent validated targets for cancer therapy and remain the subject of intensive investigation. Both EGFR and HER2 are targets found on cancer cells, whereas VEGF is a target that acts in the tumour microenvironment. Clinical studies are focusing on how to best incorporate targeted therapy into current treatment regimens and other studies are exploring whether different strategies for inhibiting these targets will offer greater benefit. It is clear that optimal use of targeted therapy will depend on understanding how these drugs work mechanistically, and recognising that their activities may differ across patient populations, tumour types and disease stages, as well as when and how they are used in cancer treatment. The results achieved with targeted therapies to date are promising, although they illustrate the need for additional preclinical and clinical study.

Robson, S., S. Pelengaris, et al. (2006). “c-Myc and downstream targets in the pathogenesis and treatment of cancer.” Recent Patents Anticancer Drug Discov 1(3): 305-26.

The c-Myc oncoprotein is a master regulator of genes involved in diverse cellular processes. Situated upstream of signalling pathways regulating cellular replication/growth as well as apoptosis/growth arrest, c-Myc may help integrate processes determining cell numbers and tissue size in physiology and disease. In cancer, this ‘dual potential’ allows c-Myc to act as its own tumour suppressor. Evidently, given that deregulated expression of c-Myc is present in most, if not all, human cancers (Table 1) and is associated with a poor prognosis, by implication these in-built ‘failsafe’ mechanisms have been overcome. To explore the complex activity of c-Myc and its potential as a therapeutic target ‘post-genome era’ technologies for determining global gene expression alongside advanced new models for the study of tumourigenesis in vivo have proved invaluable. Thus, many recent studies have provided encouragement for the therapeutic targeting of c-Myc in cancer and have revealed new protein targets for manipulating aspects of c-Myc activity. The remarkable regression of even advanced and genetically unstable tumours, seen following deactivation of c-Myc in various models is particularly exciting. This review will discuss what is known about the role of c-Myc in growth deregulation and cancer and will conclude with a discussion of the most promising recent developments in Myc-targeted therapeutics.

Rupnarain, C., Z. Dlamini, et al. (2004). “Colon cancer: genomics and apoptotic events.” Biol Chem 385(6): 449-64.

Colon cancer is the third most common cancer globally. The risk of developing colon cancer is influenced by a number of factors that include age and diet, but is primarily a genetic disease, resulting from oncogene over-expression and tumour suppressor gene inactivation. The induction and progression of the disease is briefly outlined, as are the cellular changes that occur in its progression. While colon cancer is uniformly amenable to surgery if detected at the early stages, advanced carcinomas are usually lethal, with metastases to the liver being the most common cause of death. Oncogenes and genetic mutations that occur in colon cancer are featured. The molecules and signals that act to eradicate or initiate the apoptosis cascade in cancer cells, are elucidated, and these include caspases, Fas, Bax, Bid, APC, antisense hTERT, PUMA, 15-LOX-1, ceramide, butyrate, tributyrin and PPARgamma, whereas the molecules which promote colon cancer cell survival are p53 mutants, Bcl-2, Neu3 and COX-2. Cancer therapies aimed at controlling colon cancer are reviewed briefly.

Scagliotti, G. V. and S. Novello (2003). “Pemetrexed and its emerging role in the treatment of thoracic malignancies.” Expert Opin Investig Drugs 12(5): 853-63.

Pemetrexed (Alimta); Eli Lilly and Co., Indianapolis, IN, USA) is a unique multitargeted antifolate that inhibits at least three enzymes, thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase. This novel drug is being evaluated in a comprehensive clinical programme for use in both front-line and second-line therapies. It has shown broad activity in a number of solid tumours, including colon cancer, breast cancer, lung cancer, head and neck, cervical cancer and others. While a number of antifolates have been evaluated in clinical trials, further development has been stopped or delayed by the occurrence of life-threatening toxicities. Similar trends were also initially observed with pemetrexed as well, but investigators later showed that these toxicities could be minimised with folic acid and vitamin B(12) supplementation included in the treatment regimen. Preliminary data indicate that this supplementation does not hamper drug efficacy in most tumour types and in many cases, supplemented patients exhibit improved clinical outcome. Here, the current data for pemetrexed in treating thoracic malignancies are reviewed, with special focus on malignant pleural mesothelioma and non-small cell lung cancer.

Schmittgen, T. D., A. Koolemans-Beynen, et al. (1992). “Effects of 5-fluorouracil, leucovorin, and glucarate in rat colon-tumor explants.” Cancer Chemother Pharmacol 30(1): 25-30.

In a previous study, we showed that 5-fluorouracil (FU) is active against the dimethylhydrazine-induced colon tumor in rats; a 7-day infusion of FU at 30 mg/kg daily produced 85% tumor-free cures. The present study examined the effects of FU alone and in combination with leucovorin (LV) or D-glucarate (GT) using an ex vivo system that maintained the growth of the rat colon-tumor explants on collagen gels. The labeling index (LI) was determined by the incorporation of [3H]-thymidine and autoradiography. The mean LI of the untreated control was 64.8% +/- 19.8%. The IC50, IC90, and IC95 values following a 7-day exposure to FU were 0.36, 0.75, and 1.22 microM, respectively. In comparison, the steady-state FU concentration required to produce 67% tumor-free cures in rats following a 7-day infusion is 1.54 microM. LV alone did not produce any antiproliferative effect at concentrations as high as 10 microM. The addition of LV at concentrations of 0.001-10 microM did not significantly reduce the IC50 of FU. The lack of effect of LV may have been due to tissue saturation with folate provided in the culture medium. GT alone reduced the tumor LI by 20%-30% at concentrations of 0.1-10 microM. GT enhanced the effect of FU. As compared with FU alone, the addition of GT at concentrations of 0.1 and 1.0 microM reduced the IC50 of FU by 47% and 60% to 0.21 and 0.16 microM, respectively. Assessment of the potentiation of the inhibitory effect of FU by GT using two-way analysis of variance and the isobologram method indicated a significant synergistic interaction between FU and GT. This interaction occurred within the FU concentration range of 0.08 and 0.4 microM. In summary, these data indicate that (a) the IC values for FU are comparable in tumor explants and in rats, suggesting that the effects in cultured tumors reflect those in intact animals; (b) GT alone showed antitumor activity, albeit relatively minor as compared with FU; (c) FU and GT exhibited synergistic activity, which was most pronounced at FU concentrations that produced submaximal activity (less than 30% inhibition of tumor LI); and (d) GT and LV had different effects on the growth inhibition by FU, suggesting that GT acts by a mechanism different from the thymidylate synthase-directed effect of FU and LV.

Sethi, G., B. Sung, et al. (2008). “Nuclear factor-kappaB activation: from bench to bedside.” Exp Biol Med (Maywood) 233(1): 21-31.

Nuclear factor-kappaB (NF-kappaB) is a proinflammatory transcription factor that has emerged as an important player in the development and progression of malignant cancers. NF-kappaB targets genes that promote tumor cell proliferation, survival, metastasis, inflammation, invasion, and angiogenesis. Constitutive or aberrant activation of NF-kappa is frequently encountered in many human tumors and is associated with a resistant phenotype and poor prognosis. The mechanism of such persistent NF-kappaB activation is not clear but may involve defects in signaling pathways, mutations, or chromosomal rearrangements. Suppression of constitutive NF-kappaB activation inhibits the oncogenic potential of transformed cells and thus makes NF-kappaB an interesting new therapeutic target in cancer.

Shaw, R. J., M. Kosmatka, et al. (2004). “The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress.” Proc Natl Acad Sci U S A 101(10): 3329-35.

AMP-activated protein kinase (AMPK) is a highly conserved sensor of cellular energy status found in all eukaryotic cells. AMPK is activated by stimuli that increase the cellular AMP/ATP ratio. Essential to activation of AMPK is its phosphorylation at Thr-172 by an upstream kinase, AMPKK, whose identity in mammalian cells has remained elusive. Here we present biochemical and genetic evidence indicating that the LKB1 serine/threonine kinase, the gene inactivated in the Peutz-Jeghers familial cancer syndrome, is the dominant regulator of AMPK activation in several mammalian cell types. We show that LKB1 directly phosphorylates Thr-172 of AMPKalpha in vitro and activates its kinase activity. LKB1-deficient murine embryonic fibroblasts show nearly complete loss of Thr-172 phosphorylation and downstream AMPK signaling in response to a variety of stimuli that activate AMPK. Reintroduction of WT, but not kinase-dead, LKB1 into these cells restores AMPK activity. Furthermore, we show that LKB1 plays a biologically significant role in this pathway, because LKB1-deficient cells are hypersensitive to apoptosis induced by energy stress. On the basis of these results, we propose a model to explain the apparent paradox that LKB1 is a tumor suppressor, yet cells lacking LKB1 are resistant to cell transformation by conventional oncogenes and are sensitive to killing in response to agents that elevate AMP. The role of LKB1/AMPK in the survival of a subset of genetically defined tumor cells may provide opportunities for cancer therapeutics.

Sibilia, M., R. Kroismayr, et al. (2007). “The epidermal growth factor receptor: from development to tumorigenesis.” Differentiation 75(9): 770-87.

The epidermal growth factor receptor (EGFR) is activated by many ligands and belongs to a family of tyrosine kinase receptors, including ErbB2, ErbB3, and ErbB4. These receptors are de-regulated in many human tumors, and EGFR amplification, overexpression, and mutations are detected at a high frequency in carcinomas and glioblastomas, which are tumors of epithelial and glial origin, respectively. From the analysis of EGFR-deficient mice, it seems that the cell types mostly affected by the absence of EGFR are epithelial and glial cells, the same cell types where the EGFR is found to be overexpressed in human tumors. Therefore, it is important to define molecularly the function of EGFR signaling in the development of these cell types, because this knowledge will be of fundamental importance to understand how aberrant EGFR signaling can lead to tumor formation and progression. A molecular understanding of the pathways that control the development of a given tissue or cell type will also provide the basis for developing better combination therapies targeting different key components of the EGFR signaling network in the respective cancerous cells. Here, we will review the current knowledge, mostly derived from the analysis of genetically modified mice and cells, about the function of the EGFR in specific organs and tissues and in sites where the EGFR is found to be overexpressed in human tumors.

Sinicrope, F. A. (2006). “Targeting cyclooxygenase-2 for prevention and therapy of colorectal cancer.” Mol Carcinog 45(6): 447-54.

Cyclooxygenase-2 (COX-2) is an inducible enzyme that regulates prostaglandin synthesis and is overexpressed at sites of inflammation and in several epithelial cancers. A causal link for COX-2 in epithelial tumorigenesis was shown in genetically manipulated animal models of colon and breast carcinoma. Studies have elucidated the regulation of COX-2 expression and have identified EP receptors through which prostanoids exert their biological effects. Mechanistic studies indicated that COX-2 is involved in apoptosis resistance, angiogenesis, and tumor cell invasiveness, which appear to contribute to its effects in tumorigenesis. Furthermore, forced COX-2 expression has been shown to suppress apoptosis by modulating the level of death receptor 5 (DR5) and this effect was reversed by a COX inhibitor. COX enzymes are targets for cancer prevention as shown by the observation that nonselective COX and selective COX-2 inhibitors have been reported to effectively prevent experimental colon cancer and can regress colorectal polyps in patients with familial adenomatous polyposis. This review will focus on the role of COX-2 as a target for the prevention and treatment of human colorectal cancer.

Sriram, N., S. Kalayarasan, et al. (2008). “Diallyl sulfide induces apoptosis in Colo 320 DM human colon cancer cells: involvement of caspase-3, NF-kappaB, and ERK-2.” Mol Cell Biochem 311(1-2): 157-65.

Chemoprevention is regarded as one of the most promising and realistic approaches in the prevention of human cancer. Diallyl sulfide (DAS), an organosulfur component of garlic has been known for its chemopreventive activities against various cancers and also in recent years, numerous investigations have shown that sulfur-containing compounds induce apoptosis in multiple cell lines and experimental animals. Thus the present study was focused to elucidate the anticancerous effect and the mode of action of DAS against Colo 320 DM colon cancer cells. DAS induced apoptosis in Colo 320 DM cells was revealed by flow cytometer analysis and phosphatidyl serine exposure. DAS also promoted cell cycle arrest substantially at G2/M phase in Colo 320 DM cells. The production of reactive oxygen intermediates, which were examined by 2,7-dichlorodihydrofluorescein diacetate (H(2)DCF-DA), increased with time, after treatment with DAS. The activities of alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were decreased upon DAS treatment, which shows the antiproliferative and the cytotoxic effects, respectively. The expression of NF-kappaB was upregulated in DAS treated cells, compared to normal cells. Further, DAS promoted the expression of caspase-3 and suppression of Extracellular Regulatory Kinase-2 (ERK-2) activity in Colo 320 DM cells that was determined by Western blot analysis. In conclusion, DAS increased the production of ROS, caused cell cycle arrest, decreased cell proliferation and induced apoptosis in Colo 320 DM cells. Thus, this study put forward DAS as a drug that can possibly be used to treat cancers.

Sundaram, S. G. and J. A. Milner (1996). “Diallyl disulfide suppresses the growth of human colon tumor cell xenografts in athymic nude mice.” J Nutr 126(5): 1355-61.

The present studies examined the anti-proliferative effects of diallyl disulfide (DADS) on the growth of human colon tumor cell line, HCT-15, xenografts in 6-wk-old female NCr nu/nu mice with an initial body weight of 20-22 g. Intraperitoneal injection of 1 mg DADS thrice weekly reduced tumor volume by 69% (P < 0.05) without apparent ill consequences such as altered growth of the host. Providing this quantity of DADS intragastrically also inhibited growth of the HCT-15 tumor. At equivalent DADS dosages, intraperitoneal treatment was proportionately more effective (P < 0.05) in reducing tumor growth than gastric intubation. Tumor inhibition caused by DADS (0.5 mg thrice weekly) was similar to that occurring with 5-fluorouracil (5-FU) treatment (0.5 mg thrice weekly). Combining DADS and 5-FU was no more effective in inhibiting tumor growth than using either compound alone. However, concurrent DADS treatment significantly (P < 0.05) inhibited the depression in leukocyte counts and spleen weight and prevented the elevated plasma urea caused by 5-FU treatment. These data suggest that DADS, a constituent of garlic oil, reduces the toxicity of 5-FU and is an effective antitumorigenic agent against xenografts resulting from an established human colon tumor cell line.

Takahashi, Y. and Y. Niitsu (1994). “[Glutathione S transferases-pi].” Gan To Kagaku Ryoho 21(7): 945-51.

It has been known that many drug resistant factors including p-glycoprotein related to anticancer drug resistance. It is assumed that Glutathione s-transferase (GST) is one of the resistant factors. In this present study, we examined the relationship between GST (especially GST-pi) and drug resistance, and also possibility of overcoming of drug resistance for GST-pi related drug resistance. We studied whether GST-pi directly related to anticancer drug resistance by transfection of GST-pi antisense cDNA into human colonic cancer cell line (M 7609). By transfection, cytosolic GST-pi concentrations decreased and sensitivity for adriamycin increased. It was confirmed that GST-pi directly related to some anticancer drug resistance including adriamycin. Moreover, we also have found that ketoprofen, which is an inhibitor of GST-pi activity, increased Adriamycin sensitivity. That is, partial overcoming of drug resistance was obtained. In future, it will be expected that GST-pi inhibitors etc are tried for overcoming of drug resistance.

Veeravagu, A., A. R. Hsu, et al. (2007). “Vascular endothelial growth factor and vascular endothelial growth factor receptor inhibitors as anti-angiogenic agents in cancer therapy.” Recent Patents Anticancer Drug Discov 2(1): 59-71.

New blood vessel formation (angiogenesis) is fundamental to the process of tumor growth, invasion, and metastatic dissemination. The vascular endothelial growth factor (VEGF) family of ligands and receptors are well established as key regulators of these processes. VEGF is a glycoprotein with mitogenic activity on vascular endothelial cells. Specifically, VEGF-receptor pathway activation results in signaling cascades that promote endothelial cell growth, migration, differentiation, and survival from pre-existing vasculature. Thus, the role of VEGF has been extensively studied in the pathogenesis and angiogenesis of human cancers. Recent identification of seven VEGF ligand variants (VEGF [A-F], PIGF) and three VEGF tyrosine kinase receptors (VEGFR- [1-3]) has led to the development of several novel inhibitory compounds. Clinical trials have shown inhibitors to this pathway (anti-VEGF therapies) are effective in reducing tumor size, metastasis and blood vessel formation. Clinically, this may result in increased progression free survival, overall patient survival rate and will expand the potential for combinatorial therapies. Having been first described in the 1980s, VEGF patenting activity since then has focused on anti-cancer therapeutics designed to inhibit tumoral vascular formation. This review will focus on patents which target VEGF-[A-F] and/or VEGFR-[1-3] for use in anti-cancer treatment.

Versantvoort, C. H., H. J. Broxterman, et al. (1995). “Regulation by glutathione of drug transport in multidrug-resistant human lung tumour cell lines overexpressing multidrug resistance-associated protein.” Br J Cancer 72(1): 82-9.

Wang, C. Z., X. Luo, et al. (2007). “Notoginseng enhances anti-cancer effect of 5-fluorouracil on human colorectal cancer cells.” Cancer Chemother Pharmacol 60(1): 69-79.

PURPOSE: Panax notoginseng is a commonly used Chinese herb. Although a few studies have found that notoginseng shows anti-tumor effects, the effect of this herb on colorectal cancer cells has not been investigated. 5-Fluorouracil (5-FU) is a chemotherapeutic agent for the treatment of colorectal cancer that interferes with the growth of cancer cells. However, this compound has serious side effects at high doses. In this study, using HCT-116 human colorectal cancer cell line, we investigated the possible synergistic anti-cancer effects between notoginseng flower extract (NGF) and 5-FU on colon cancer cells. METHODS: The anti-proliferation activity of these modes of treatment was evaluated by MTS cell proliferation assay. Apoptotic effects were analyzed by using Hoechst 33258 staining and Annexin-V/PI staining assays. The anti-proliferation effects of four major single compounds from NGF, ginsenosides Rb1, Rb3, Rc and Rg3 were also analyzed. RESULTS: Both 5-FU and NGF inhibited proliferation of HCT-116 cells. With increasing doses of 5-FU, the anti-proliferation effect was slowly increased. The combined usage of 5-FU 5 microM and NGF 0.25 mg/ml, significantly increased the anti-proliferation effect (59.4 +/- 3.3%) compared with using the two medicines separately (5-FU 5 microM, 31.1 +/- 0.4%; NGF 0.25 mg/ml, 25.3 +/- 3.6%). Apoptotic analysis showed that at this concentration, 5-FU did not exert an apoptotic effect, while apoptotic cells induced by NGF were observed, suggesting that the anti-proliferation target(s) of NGF may be different from that of 5-FU, which is known to inhibit thymidilate synthase. CONCLUSIONS: This study demonstrates that NGF can enhance the anti-proliferation effect of 5-FU on HCT-116 human colorectal cancer cells and may decrease the dosage of 5-FU needed for colorectal cancer treatment.

Wierstra, I. and J. Alves (2008). “The c-myc promoter: still MysterY and challenge.” Adv Cancer Res 99: 113-333.

The transcription factor c-Myc is a key regulator of cell proliferation, cell growth, differentiation, and apoptosis. Deregulated c-myc expression possesses a high transformation potential and the proto-oncogene c-myc represents a promising target in anticancer therapy. This review on the c-myc promoter describes its organization, the different levels of its normal regulation (including initiation and elongation of transcription, the dual P1/P2 promoters, chromatin structure, c-Myc autosuppression) as well as its deregulation in Burkitt’s lymphoma. Furthermore, it summarizes the many different transcription factors, signal transduction pathways, and feedback loops that activate or repress c-myc transcription. Finally, a concept for regulation of the c-myc promoter in different biological settings, for example, immediate-early induction, constant expression throughout the cell cycle in continuously cycling cells, repression during terminal differentiation and deregulation in cancer, is formulated.

Woerner, S. M., M. Kloor, et al. (2005). “Microsatellite instability of selective target genes in HNPCC-associated colon adenomas.” Oncogene 24(15): 2525-35.

Microsatellite instability (MSI) occurs in most hereditary nonpolyposis colorectal cancers (HNPCC) and less frequently in sporadic tumors as the result of DNA mismatch repair (MMR) deficiency. Instability at coding microsatellites (cMS) in specific target genes causes frameshift mutations and functional inactivation of affected proteins, thereby providing a selective growth advantage to MMR deficient cells. At present, little is known about Selective Target Gene frameshift mutations in preneoplastic lesions. In this study, we examined 30 HNPCC-associated MSI-H colorectal adenomas of different grades of dysplasia for frameshift mutations in 26 cMS-bearing genes, which, according to our previous model, represent Selective Target genes of MSI. About 30% (8/26) of these genes showed a high mutation frequency (> or =50%) in colorectal adenomas, similar to the frequencies reported for colorectal carcinomas. Mutations in one gene (PTHL3) occurred significantly less frequently in MSI adenomas compared to published mutation rates in MSI carcinomas (36.0 vs 85.7%, P=0.023). Biallelic inactivation was observed in nine genes, thus emphasizing the functional impact of cMS instability on MSI tumorigenesis. Some genes showed a high frequency of frameshift mutations already at early stages of MSI colorectal tumorigenesis that increased with grade of dysplasia and transition to carcinoma. These include known Target Genes like BAX and TGFBR2, as well as three novel candidates, MACS, NDUFC2, and TAF1B. Overall, we have identified genes of potential relevance for the initiation and progression of MSI tumorigenesis, thus representing promising candidates for novel diagnostic and therapeutic approaches directed towards MMR-deficient tumors.

Wrzesinski, S. H., M. L. McGurk, et al. (2007). “Successful desensitization to oxaliplatin with incorporation of calcium gluconate and magnesium sulfate.” Anticancer Drugs 18(6): 721-4.

Since the results of the MOSAIC trial demonstrated an improved disease-free survival in stage III colorectal patients treated with oxaliplatin combined with 5-fluorouracil and folinic acid when they were compared with those treated with 5-fluorouracil and folinic acid alone, the addition of this organoplatin to 5-fluorouracil and folinic acid has become first-line adjuvant treatment for stage III colorectal cancer. Unfortunately, there is a small population of patients who develop grade III/IV hypersensitivity reactions to oxaliplatin which, until recently, have interfered with further treatment with oxaliplatin-containing regimens. Successful oxaliplatin desensitization protocols for patients having severe oxaliplatin hypersensitivity reactions have been reported. However, none of these protocols, have incorporated magnesium and calcium salts. Retrospective data has suggested that pretreating colorectal cancer patients with magnesium sulfate and calcium gluconate before the administration of oxaliplatin may reduce the incidence of neurotoxicities induced by this drug. Therefore, we modified a previously published oxaliplatin-desensitization protocol by incorporating intravenous calcium gluconate and magnesium sulfate, and report a patient with stage IIIc colorectal cancer and prior severe hypersensitivity reactions to oxaliplatin who underwent successful oxaliplatin desensitization using this protocol.

Wynter, M. P., S. T. Russell, et al. (2004). “Effect of n-3 fatty acids on the antitumour effects of cytotoxic drugs.” In Vivo 18(5): 543-7.

BACKGROUND: n-3 fatty acids are increasingly being administered to cancer patients for the treatment of cachexia, and it is thus important to know of any potential interactions with ongoing cytotoxic drug therapy. MATERIALS AND METHODS: For this reason eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were administered to mice bearing the cachexia-inducing MAC16 colon adenocarcinoma, and the effect of epothilone, gemcitabine, 5-fluorouracil and cyclophosphamide on tumour growth and body weight determined. RESULTS: Epothilone alone had a minimal effect on tumour growth rate, but this was potentiated by DH4, while for 5-fluorouracil and cyclophosphamide tumour growth inhibition was enhanced by EPA. The antitumour effect of gemcitabine was not altered by either fatty acid. EPA arrested the development of cachexia, while DHA had no effect and the same was true for their effect on tumour growth rate. The anticachectic effect of EPA was only seen in combination with 5-fluorouracil. CONCLUSION: These results suggest that n-3 fatty acids do not interfere with the action of chemotherapy and may potentiate the effect of certain agents.

Zaman, G. J., J. Lankelma, et al. (1995). “Role of glutathione in the export of compounds from cells by the multidrug-resistance-associated protein.” Proc Natl Acad Sci U S A 92(17): 7690-4.

INTRODUCTION
Chemotherapy is a critical part of care for lung cancer patients. However, there are some notable drawbacks to chemotherapy, such as lung cancer cells becoming resistant to treatment or side effects becoming debilitating and intolerable.

Although not commonly addressed in clinical consultation, scientific evidence suggests that combining certain chemotherapy treatments with specific antioxidants at defined dosages can help improve drug effectiveness, or may reduce side effect severity.

This issue is important because it has long been the opinion of many practicing oncologists that antioxidants should simply not be used concurrently with chemotherapy in the belief that the combination might inhibit chemotherapy effectiveness. This reluctance stems, in part, from the fact that some chemotherapy drugs work by strongly promoting oxidation. This is especially the case for the class of chemotherapy drugs called anthracyclines (Adriamycin and epirubicin), the alkylating agents (chlorambucil, cyclophosphamide, thiotepa, and busulfan), and the platinum drugs (cisplatin and carboplatin). Antioxidants, by definition, inhibit oxidation, so it was believed that antioxidants would prevent these chemotherapy drugs from working properly.

The controversy around using antioxidants together with chemotherapy is based, in part, on some studies of other cancer types and chemotherapy drugs that show how depleting glutathione, which is a natural antioxidant in the body, can enhance the treatment effect of chemotherapy. (Meijer, Mulder et al. 1990; Mans, Schuurhuis et al. 1992; Doyle, Ross et al. 1995; Versantvoort, Broxterman et al. 1995; Zaman, Lankelma et al. 1995; Kurokawa, Nishio et al. 1997; Lee, Park et al. 2004) Although this has led many oncologists to believe that all antioxidants should not be combined with chemotherapy, there are numerous laboratory and human studies showing how combining chemotherapy with antioxidants can indeed be helpful.

In this systematic review in which we searched for every paper on the combination of antioxidants and chemotherapy for lung cancer, we found only two laboratory (and no human) studies demonstrating a harmful combined effect.

Chemotherapy drugs that cause high levels of “oxidative stress” are thought to rely in part on oxidative stress to kill cancer cells, but other effects of that oxidative stress may also be getting in the way of the effectiveness of the chemotherapy. This is because oxidative stress slows cell replication and chemotherapy relies on fast cancer cell replication to be effective because it is during replication that chemotherapy kills cancer cells. (Conklin 2000) One approach to addressing this problem is the addition of certain antioxidants at specific dosages to lessen oxidative stress, thus making the chemotherapy treatment more effective. (Perumal, Shanthi et al. 2005)

The interaction between chemotherapy and antioxidants is more complex, however, than simply promoting and inhibiting oxidative stress. There are several mechanisms by which chemotherapy drugs function and antioxidants also have a number of different effects on the body. Each antioxidant has a different interaction with chemotherapy and this effect can even change based upon the dosage used.

In the end, the question is not whether antioxidants should be used in combination with chemotherapy but rather which should be used and at what dosages.

PURPOSE OF THIS PAPER
In this evidence-based review article, we discuss the results of current research showing how antioxidants may enhance or, in some cases, inhibit the therapeutic action of specific chemotherapy drugs used in the treatment of lung cancer. Some of these antioxidants may also reduce chemotherapy side effects or inhibit chemotherapy resistance in lung cancer cells. Finally, some of these antioxidants have been found to be useful for restoring the natural antioxidants in the body, which are often depleted after the completion of chemotherapy.

HOW NUTRIENT DEPLETION FROM CHEMOTHERAPY CAN OCCUR
Chemotherapy can cause nutrient depletion from two major side effects. One is nausea and vomiting, making it more difficult for the patient to maintain adequate nutrient intake. Another is toxicity to cells in the gastrointestinal tract, making it more difficult for the intestines to adequately absorb nutrients. Antioxidants are not the only nutrients to become depleted; vitamins, minerals, amino acids, and fatty acids may also be compromised, especially in patients who have suffered these side effects for a prolonged amount of time. For example, the following chemotherapy drugs damage the cells in the gastrointestinal system and can cause considerable nausea and vomiting: cisplatin, cyclophosphamide, daunorubicin, doxorubicin, mitomycin, mitoxantrone, paclitaxel, and vinorelbine.

METHODS
We searched for clinical or laboratory data published in peer-reviewed medical journals, conducted by cancer researchers in universities and medical research facilities from around the world, most published in prestigious, peer-reviewed journals. Some of these studies are still in early stages and include only laboratory or animal data, while others have advanced to include human volunteers.

We organized these data into the major categories of specific chemotherapy drugs. Within each section for a specific drug are found the research on combinations of that drug with various antioxidants, grouped by the name of the antioxidant in alphabetical order. We also point out specifically which studies were conducted in a laboratory (i.e. using cancer cell cultures), which were conducted using animals, and which were conducted with human volunteers. As each antioxidant appears in the paper for the first time, we provide some introduction to the antioxidant including what food sources naturally contain it, other common applications in clinical use, and typical dosages. The dosages given are not necessarily appropriate for all patients and should be individualized with practitioner guidance.

RESULTS

Carboplatin (Paraplatin)

MELATONIN
Melatonin is a hormone that is released from the pineal gland in the evening and promotes normal sleep; its secretion diminishes significantly with age. It is known to help maintain cell health and many people take it to improve sleep. It is also known to reduce metastasis in cancer patients. In most published studies, melatonin shows a beneficial effect, although it has been reported that in a small proportion of people, melatonin can paradoxically cause sleep disturbance. In others, there can be residual daytime drowsiness, which is usually resolved by using a lower dose.

» Melatonin: Typical dosages range from 1 mg to 20 mg. If aiming for a high dosage, one should start with 1 mg and increase the dosage slowly by 1 mg every 3 to 7 days. The ideal is to achieve peak blood levels of melatonin at about 2am. To do so, one can take the melatonin at bedtime, ideally between 9pm and 10pm.

Twenty previously untreated patients with inoperable small cell and non-small cell lung cancer were randomized in a double blind study to receive either chemotherapy alone or chemotherapy in combination with melatonin (40 mg per day). Chemotherapy consisted of carboplatin and etoposide. The trial investigated the potential of melatonin to protect against chemotherapy-induced toxicity to the bone marrow, where blood cells are produced. There was no significant difference between the groups in blood counts. (Ghielmini, Pagani et al. 1999)

MULTI-COMPOUND REGIMEN
In the following study, investigators combined the antioxidants vitamin C, vitamin E, and beta-carotene with the chemotherapy drugs paclitaxel and carboplatin.

Vitamin C (Ascorbic Acid)
Vitamin C, also called ascorbic acid, is a nutrient that humans cannot synthesize and must obtain from the diet. Almost all fresh vegetables and fruits are sources of vitamin C. Broccoli, cauliflower, citrus fruits, and tomatoes are examples of food sources particularly high in vitamin C.

» Vitamin C: Typical doses range from 60 mg to 1000 mg a day or up to bowel tolerance.

Vitamin E, Alpha Tocopherol
Vitamin E includes several related compounds: Tocopherols and tocotrienols, each of which have four subtypes of alpha, beta, gamma, and delta. Previously, only alpha-tocopherol was considered important, however each type has unique contributions to health. The best dietary sources of vitamin E are considered to be unrefined, cold-pressed vegetable oils such as wheat germ, sunflower seed, and olive oil as well as raw or sprouted seeds, nuts, and grains.

» Vitamin E: Avoid synthetic vitamin E, such as alpha-tocopherol or succinate. Seek out the mixed tocopherols, including tocopherols and tocotrienols. Typical dosage ranges from 50 IU to 800 IU daily.

Beta-Carotene
Beta-carotene is the most well known carotenoid, producing the red, orange, and yellow pigments in fruits and vegetables. It is a precursor of vitamin A, but also has its own physiological functions. (See “What about Lung Cancer and Beta-Carotene” sidebar at the end of this article.)

» Beta-carotene: Typical supplemental doses range from 5000 to 25,000 IU (3 to 15 mg) daily.

In a human lung squamous cell carcinoma cell line, the antioxidant mixture of vitamin C, vitamin E, and beta-carotene enhanced the treatment effect of paclitaxel and carboplatin. Paclitaxel followed by carboplatin 24 hours later led to an apoptosis (cancer cell killing) rate of 54%. In contrast, the vitamins administered together with paclitaxel and 24 hours later by carboplatin led to a 70% apoptosis rate. This effect was further enhanced to an 89% apoptosis rate by pretreatment with the vitamins 24 hours before paclitaxel, then followed another 24 hours later by carboplatin. (Pathak, Singh et al. 2002)

In a follow up human trial, the same combination of chemotherapy and antioxidants was tested in 136 previously untreated patients with advanced stage IIIB and IV non-small cell lung cancer. Patients were randomized to receive chemotherapy alone (paclitaxel and carboplatin) or chemotherapy in combination with ascorbic acid 6100 mg per day, dl-alpha-tocopherol (vitamin E) 1050 mg per day, and beta-carotene 60 mg per day. The response (tumor size reduction) rate in the chemotherapy-only group was 33%, while in the combination group was 37%. Overall survival (OS) was 32.9% at one year in the chemotherapy-alone group and 39.1% in the combination group. Median survival was 9 months in the chemotherapy-alone group and 11 months in the combination group. Toxicity was similar between the two groups. Although the difference in effectiveness was not statistically significant, it may nevertheless still be clinically significant, offering a modest improvement in treatment response and survival. Furthermore, the result of this study does not support the concern that these high-doses of antioxidants compromise the efficacy of paclitaxel-carboplatin combination chemotherapy. (Pathak, Bhutani et al. 2005)

Cisplatin (Platinol)

ASTRAGALUS
Astragalus is a tonic herb and the roots have been used for over 2000 years in Chinese medicine. It is used in the west for heart disease and to support the immune system.

» Astragalus: Typical dosages of the dried root range from 10 to 15 g daily by decoction, or as an extract 10 to 20 mL daily.

The Pine Street Foundation’s 2006 published meta-analysis has shown that adding Chinese herbal formulas based on the herb Astragalus membranaceus (Huang Qi) to cisplatin-based chemotherapy reduced risk of death at 12 months by 33%, when compared to cisplatin-based chemotherapy alone. The increase in tumor response ranged between 34% and 76% depending on the herbal formula used. (McCulloch, See et al. 2006)

DOCOSAHEXAENOIC ACID (DHA)
Omega-3 fatty acids come from several different sources and in several different forms. Sources include blue-green algae, fish oil, and eggs, from which docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) can be derived. It is used as a supplement in clinical practice for many therapeutic uses, some of which include cancer, heart disease, depression, diabetes, and multiple sclerosis.

» Omega 3 Polyunsaturated Fatty Acids (PUFA, from fish oil including DHA/EPA): Typical dosage range is from 1,000 mg to 10,000 mg daily. When finding a fish oil supplement, it is important to identify brands that can provide assurance that they have tested for heavy metals, such as mercury.

In a laboratory study of human small-cell lung cancer cells that were resistant to cisplatin, supplementing with DHA led to an almost three-fold decrease in the ability of tumor cells to be resistant to chemotherapy. In cancer cells that were not resistant to cisplatin treatment, DHA did not increase the treatment effectiveness of cisplatin. (Timmer-Bosscha, Hospers et al. 1989)

GENISTEIN
Genistein is an isoflavone found in legumes, especially soybeans. Isoflavones are antioxidants that counteract the damaging effects of free radicals in body tissues. Isoflavones, such as genistein, also have anti-angiogenic effects, blocking the formation of new blood vessels needed to support the growth of tumors.

» Genistein: A good product will use organic, non-GMO genistein. To achieve anti-tumor effects, the target daily dose, based on animal studies and calculations for similar human dosage, is between 100 mg and 1100 mg. (Boik 2001) One cup of soy milk will contain, on average, about 45 mg of genistein and the other related isoflavones.

Genistein was used in combination with cisplatin, docetaxel, or doxorubicin in the treatment of non-small cell lung cancer cells in a laboratory study. The treatment effect was significantly greater when genistein was used together with cisplatin, docetaxel, or doxorubicin than any of the chemotherapy agents alone. A smaller dose of chemotherapy was applied in the combined treatment and, despite the smaller dose, the treatment was more effective with genistein. The mechanism was through inactivation of NF-kappaB by genistein. (Li, Ahmed et al. 2005) Activation of NF-kappaB (a type of protein complex) plays a role in drug resistance in cancer cells in some chemotherapy agents, including cisplatin. (Yeh, Chuang et al. 2002)

GINSENOSIDE Rh2
Ginsenosides are an active ingredient derived from ginseng, one of the most widely known herbal medicines in the world and commonly used for its immune stimulating and anti-tumor properties. (Boik 2001)

» White American Ginseng Extract: Commonly used dosage levels of ginseng extract range between 200 and 1000 mg.

In a study using human lung adenocarcinoma, Ginsenoside Rh2 reversed resistance to cisplatin. In cisplatin resistant cells, the addition of Ginsenoside Rh2 decreased by three-fold the amount of cisplatin needed to achieve the same treatment effect of cisplatin alone. (Hu, Hu et al. 2005)

MELATONIN
Researchers from Italy published a study in 2007 about non-small cell lung cancer patients receiving cisplatin and etoposide (58 patients) or cisplatin and gemcitabine (16 patients) with or without melatonin (20 mg per day). The response rate to treatment and disease control was higher in patients treated with chemotherapy and melatonin than in patients treated with chemotherapy alone. This difference was only significant in the patients receiving cisplatin and etoposide but was not significant in the group of patients receiving cisplatin and gemcitabine. (Lissoni 2007)

In a second trial from Italy, 100 metastatic non-small cell lung cancer patients were given cisplatin and etoposide with or without melatonin (20 mg per day). The patients treated with chemotherapy and melatonin had significantly less progressive disease, had better overall tumor regression, and better 5-year survival. Three patients in the melatonin group were alive at five years after beginning treatment with chemotherapy whereas no patients were alive after two years in the chemotherapy only group. Treatment with melatonin also significantly decreased neurotoxicity, thrombocytopenia, weight loss, and asthenia. No difference was observed in alopecia and anemia. (Lissoni, Chilelli et al. 2003)

A third trial from Italy enrolled 104 metastatic non-small cell lung cancer patients who received chemotherapy treatment that consisted of cisplatin and etoposide or gemcitabine alone. Patients were randomized to receive chemotherapy alone or chemotherapy and melatonin at 20 mg per day. The response rate to chemotherapy was higher in patients treated with melatonin, although this difference was only significant in patients receiving cisplatin and etoposide but not gemcitabine. Nevertheless, one year survival was significantly higher in the patients receiving melatonin in both chemotherapy groups. (Lissoni, Barni et al. 1999)

5-METHOXYTRYPTAMINE (5-MTT)
5-methoxytryptamine (5-MTT) is a pineal hormone.

» 5-methoxytryptamine (5-MTT): Typical dosage used for cancer patients is 1 mg per day.

One hundred advanced non-small cell lung cancer patients were enrolled in a trial from Italy published in 2007 who received either chemotherapy (cisplatin and etoposide) alone or with melatonin (20 mg per day) or 5-MTT (1 mg per day). The overall response rate and disease control was significantly higher in both the melatonin and 5-MTT groups. The chemotherapy-related toxicity such as thrombocytopenia, neurotoxicity, and asthenia was significantly reduced in patients receiving chemotherapy and melatonin or 5-MTT. 5-MTT was better than melatonin at preventing anorexia. Therefore, the much lower dose of 5-MTT was as effective as melatonin in the treatment of non-small cell lung cancer. (Lissoni 2007)

In another study, 20 metastatic lung cancer patients were treated with cisplatin and etoposide and were randomized to either receive 5-MTT (1 mg per day) in addition to chemotherapy or to receive chemotherapy treatment alone. The patients treated with chemotherapy and 5-MTT had significantly reduced anemia and significantly less progressive disease in comparison to the patients treated with chemotherapy alone. (Lissoni, Malugani et al. 2003)

MULTI-COMPOUND REGIMEN
In the following study, investigators combined the antioxidants alpha-lipoic acid and N-acetyl cysteine with cisplatin, epirubicin, medroxyprogesterone acetate (a hormonal drug that is a progestin derived from the naturally occurring female hormone, progesterone), and recombinant IL-2.

Alpha-lipoic Acid
Alpha-lipoic acid is an important antioxidant that can regenerate other essential antioxidants such as vitamins C and E, coenzyme Q10, and glutathione. It is also a cofactor for some of the key enzymes (alpha-keto acid dehydrogenases) involved in generating energy. Alpha-lipoic acid comes in two forms: the “R” form is biologically active and is naturally produced by the body while the “S” form is manufactured and is less biologically active. Most alpha-lipoic supplements have a mixture of the “R” and “S” forms. Some manufacturers now make available a supplement containing pure R-dihydro-lipoic acid.

» Alpha-lipoic Acid: Typically used in a dosage range between 200 and 600 mg per day. (Boik 2001) When using the Rdihydro-lipoic acid, half the dose may be used.

N-acetyl Cysteine
N-acetyl cysteine is an efficiently absorbed and used form of the amino acid, L-cysteine. L-cysteine, L-glutamic acid, and glycine are the three amino acids that form glutathione, which is one of the most important and powerful antioxidants in the body.

» N-acetyl Cysteine: Typical dosages range between 600 and 1,800 mg per day.

A phase II clinical trial using a combination regimen including cisplatin, epirubicin, medroxyprogesterone acetate, recombinant IL-2, alpha-lipoic acid (300 mg per day), and N-acetyl cysteine (1.8 g per day) enrolled 33 non-small cell lung cancer patients: 26 with stage IIIB disease and 7 with stage IV disease. Of thirty patients whose results could be measured, the median overall survival was 15 months. The one year survival was 55.8%. The median progression free survival was 10 months. Neutropenia was the most significant symptom of toxicity from treatment; other toxicity was low. (Mantovani, Maccio et al. 2002)

QUERCETIN
Quercetin is the most abundant of the plant-derived flavonoid molecules and is a very active antioxidant. Quercetin is a flavonoid found in capers, apples, tea, onions, red grapes, citrus fruits, leafy green vegetables, cherries, and raspberries. Quercetin has anti-inflammatory activity, inhibiting allergic and inflammatory reactions. Dihydroquercetin is a supplement very similar to quercetin that may be even safer than quercetin and is most notable for its synergistic combination with vitamin C. Dihydroquercetin inhibits the oxidation of vitamin C, helping to maintain the concentration of vitamin C in the body over time. Together, vitamin C and dihydroquercetin inhibit oxidative stress and inflammation, avert complications of diabetes, protect against liver damage and hepatitis, provide immune support, and sooth irritated skin.

» Quercetin: Typical dosages range from 200 mg to 1,200 mg daily.
» Dihydroquercetin: Typical dosage is 10 mg combined with vitamin C (1000 mg).

Quercetin, when combined with cisplatin, was found to increase cell death of human non-small cell lung cancer cells by 30.2% compared to cisplatin alone in a laboratory study. (Kuhar, Sen et al. 2006) A second laboratory study also confirmed that cisplatin had a much stronger treatment effect in lung cancer cells when combined with quercetin. (Borska, Gebarowska et al. 2004)

VITAMIN D
Vitamin D includes a series of compounds exhibiting the activity of calciferol. The two most widely known types of vitamin D are ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Vitamin D3 has a greater potency and longer duration of action than vitamin D2. (Armas, Hollis et al. 2004) It is a fat-soluble vitamin and a hormone and it can either be absorbed through digestion or synthesized in the skin when exposed to sunlight.

Twenty minutes of sun exposure to the face and arms is sufficient to generate production of 600 to 1000 IU of vitamin D (during spring, summer, and fall, in temperate regions such as the San Francisco Bay Area). In an hour’s time, with sun exposure that produces mild redness of the skin, 10,000 to 20,000 IU may be generated. During spring, summer, and fall, 15 minutes of sun exposure, three times per week in the morning or late afternoon on the arms, face, and hands provides sufficient vitamin D stores to last through the end of winter (in latitudes between 35o and 50o; San Francisco is at about 37o). Sunscreen significantly reduces the synthesis of vitamin D.

Although vitamin D comes primarily from sun exposure, food sources include cod liver oil, butter, egg yolks, and vitamin D fortified milk and orange juice.

» Vitamin D: Therapeutic dosages range between 200 IU to 2000 IU per day, and doses up to 10,000 IU have been tested in clinical trials. Very high doses of vitamin D at 40,000 IU per day have been reported to result in hypercalcemia. (Vieth 1999) Lymphoma and granulomatous disease can cause vitamin D sensitivity and therefore people with these conditions should be more cautious in taking vitamin D supplements. A simple blood test for 25 hydroxy vitamin D can be used to monitor blood levels in people using vitamin D supplements.

In human non-small cell lung carcinoma cells, vitamin D compounds decreased the IC50 of cisplatin in a laboratory study (IC50 is the concentration of drug needed to achieve 50% reduction in cancer cell growth). This means that when vitamin D was added, less cisplatin was needed to achieve the same anti-tumor effect as cisplatin alone. (Pelczynska, Wietrzyk et al. 2005)

VITAMIN K
Vitamin K is a coenzyme involved in synthesis of proteins important for blood clotting and bone metabolism. Vitamin K1 is non-toxic up to 500 times the recommended daily allowance, which is 1 microgram per kilogram of body weight. It is a fat-soluble form that naturally occurs in plants and fish. Vitamin K2 is another fat-soluble form that is synthesized by the healthy bacteria in our intestines. Food sources of vitamin K2 are meat, fermented food products such as cheese, or the Japanese fermented soy product natto.

» Vitamin K: Therapeutic dosages range from 45 to 500 micrograms per day. Because vitamin K affects blood clotting, patients using anticoagulant therapy should monitor vitamin K intake with their doctor.

Vitamin K2 was found to enhance small cell lung cancer cell death caused by cisplatin in a laboratory study. (Yoshida, Miyazawa et al. 2003)

Cyclophosphamide(Cytoxan, Neosar)

BETA-1,3 D-CARBOXYMETHYLGLUCAN (BETA-1,3 D-GLUCAN)
Beta-1,3 D-glucan is derived from yeast and is a macrophage stimulator. Macrophages are an important part of the immune system.

» Beta-1,3 D-glucan: Typical dosages range from 100 to 500 mg per day.

In an animal study, Beta-1,3 D-glucan enhanced the treatment effect of cyclophosphamide in Lewis lung carcinoma. The combination treatment was more effective at inhibiting primary tumor node as well as reducing metastasis. After cyclophosphamide treatment alone, metastasis occurred in 40.9% of animals. With combined treatment, metastasis occurred in 7.5% of animals. (Falameeva, Poteryaeva et al. 2001)

GENISTEIN
In an animal study using mice with Lewis lung cancer, cyclophosphamide alone reduced tumor blood supply by 38%, while the combination of cyclophosphamide and genistein reduced tumor blood supply by 61%. (Wietrzyk, Boratynski et al. 2001)

GINSENOSIDE Rg3
A low dose schedule of cyclophosphamide was enhanced by the angiogenic inhibitor ginsenoside Rg3 in mice with Lewis lung carcinoma. Tumor growth was delayed, side effects were mitigated, survival was increased, and angiogenesis was enhanced in mice receiving combined treatment in contrast to mice receiving cyclophosphamide alone. (Zhang, Kang et al. 2006) Angiogenic inhibitors decrease the blood vessels to the tumor so that the supply of nutrients to the tumor is decreased and thus growth is inhibited.

MULTI-COMPOUND REGIMEN
In the following study, investigators combined the antioxidants vitamin A, retinoic acid, vitamin E, vitamin D, melatonin, and beta-carotene with somatostatin (a hormone that inhibits the release of various growth hormones), cyclophosphamide, and bromocriptine (a dopamine agonist that works by blocking the release of prolactin from the pituitary gland and lowering growth hormone levels).

Vitamin A & Retinoic Acid
Retinoic acid is the acidified form of vitamin A (retinol), the animal form of vitamin A. Retinoic acid is a prescription drug; the generic name is tretinoin and one of the trade names is Vesanoid. Retinol is a fat-soluble, antioxidant vitamin important for bone growth and vision. Retinol is ingested in a precursor form from animal foods and is especially plentiful in cod liver oil. Other good sources include butter and egg yolks as well as whole milk, cream, and yogurt.

» Vitamin A: Typical dosages range from 2500 IU to 25,000 IU.

Twenty-three patients with stage IIIB or IV lung adenocarcinoma whose disease had progressed after standard chemotherapy, and who also had poor quality of life, received a combination of somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide. The median overall survival was 95 days and the side effect consisted of grade 1-2 diarrhea, nausea/vomiting, and drowsiness. Fifty percent of patients experienced improved respiratory as well as general symptoms. Most of these were patients that survived longer than 95 days. (Norsa and Martino 2006)

Daunorubicin, Daunomycin (Cerubidine)

GENISTEIN , BIOCHANIN A, APIGENIN, AND QUERCETIN
In Adriamycin resistant small cell lung cancer cells, genistein, biochanin A, apigenin (an antioxidant flavonoid found in plants such as parsley, artichoke, basil, and celery), and quercetin inhibited the flow of daunorubicin out of the cancer cells. The antioxidants were not administered together as a mixture but rather tested separately with daunorubicin. (Versantvoort, Schuurhuis et al. 1993)

Docetaxel (Taxotere)

GENISTEIN
Genistein was used in combination with cisplatin, docetaxel, or doxorubicin in the treatment of non-small cell lung cancer cells in a laboratory study. The treatment effect was significantly greater when genistein was used together with cisplatin, docetaxel, or doxorubicin than any of the chemotherapy agents alone. A smaller dose of chemotherapy was applied in the combined treatment and, despite the smaller dose, the treatment was more effective with genistein. The mechanism was through inactivation of NF-kappaB by genistein. (Li, Ahmed et al. 2005) Activation of NF-kappaB plays a role in drug resistance in cancer cells in some chemotherapy agents including cisplatin. (Yeh, Chuang et al. 2002)

Doxorubicin (Adriamycin)

CURCUMIN
Curcumin is a polyphenol and is an extract of the Indian curry spice plant turmeric. Curcumin is known for its anti-tumor, antioxidant, anti-amyloid, and anti-inflammatory properties. It also promotes healthy bile excretion and healthy platelet function.

» Curcumin: The best supplements contain curcumin at 75% or higher concentration. Typical doses range from 500 mg to 4,000 mg daily. Take with meals as it can cause stomach upset when taken on an empty stomach. Bioavailability and potency are increased when combined with Bioperine, from black pepper.

A laboratory study found that curcumin prevented doxorubicin from flowing out of non-small cell lung cancer cells that were resistant to doxorubicin. Therefore, curcumin may enhance the treatment effect of doxorubicin in doxorubicin-resistant lung cancer cells in vitro. (Pesic, Markovic et al. 2006)

DOCOSAHEXAENOIC ACID (DHA)
Slight to no enhancement of treatment effect (but no decreased effect) was observed after combination treatment using doxorubicin and DHA in a laboratory study using bronchial carcinoma cell lines. Interestingly, that same combined treatment did enhance treatment effectiveness in brain cancer cell lines, underscoring the importance of combining the right antioxidant with the right drug and the appropriate cancer. (Rudra and Krokan 2001) In a second laboratory study, DHA increased the concentration of doxorubicin in small-cell lung cancer cells by 10 to 30%. Despite the increase in concentration of doxorubicin, there was no increase in treatment effect in doxorubicin sensitive cells, however there was a partial reversal of resistance in the doxorubicin resistant cells. (Zijlstra, de Vries et al. 1987)

FISH OIL
An animal study compared mice with lung cancer tumors treated with doxorubicin and a diet rich in either corn oil or fish oil. In mice that received fish oil and doxorubicin, there was significant tumor regression. In mice that received corn oil and doxorubicin, the treatment only halted the growth of the tumor. Thus fish oil was found to enhance the treatment effect of doxorubicin. (Hardman, Moyer et al. 2000)

GENISTEIN
Genistein was used in combination with cisplatin, docetaxel, or doxorubicin in the treatment of non-small cell lung cancer cells in a laboratory study. The treatment effect was significantly greater when genistein was used together with cisplatin, docetaxel, or doxorubicin than any of the chemotherapy agents alone. A smaller dose of chemotherapy was applied in the combined treatment and, despite the smaller dose, the treatment was more effective with genistein. The mechanism was through inactivation of NF-kappaB by genistein. (Li, Ahmed et al. 2005) Activation of NF-kappaB plays a role in drug resistance in cancer cells in some chemotherapy agents including cisplatin. (Yeh, Chuang et al. 2002)

MELATONIN
In a laboratory study, melatonin intensified doxorubicin effectiveness in non-small cell lung cancer cells. (Fic, Podhorska-Okolow et al. 2007)

SELENIUM
Selenium is an essential trace mineral in the body and is found in variable amounts in food depending on the soil content of selenium. Brazil nuts are the single best food source of selenium. One of its roles in the body is as an antioxidant and it is most widely known as a cancer preventive.

» Selenium (mineral): The US Adult Tolerable Upper Intake Level (UL) is 400 micrograms a day and the Lowest Observed Adverse Effects Level (LOAEL) for adults is about 900 micrograms daily. There are several different forms of selenium; Se-Methylselenocysteine is a highly bioavailable form because it is not incorporated within a protein such as the form selenomethionine. We recommend getting selenium either in the organically bound forms, such as of Se-Methylselenocysteine, or a combination of selenium compounds with L-selenomethionine, sodium selenate, selenodiglutathione, and Se-methylselenocysteine.

Selenium in combination with doxorubicin or paclitaxel enhanced the chemotherapeutic effect of doxorubicin and paclitaxel in human squamous lung cancer cells in a laboratory study. (Vadgama, Wu et al. 2000)

In human small cell lung carcinoma cells that had developed resistance to doxorubicin, treatment with selenium caused significant apoptosis. In contrast, the cells that were sensitive to doxorubicin did not respond to treatment with selenium as strongly. It is important to note that this study does not comment on the combination of doxorubicin and selenium as a combined treatment, but rather only selenium treatment of cancer cells that are resistant or sensitive to doxorubicin. (Jonsson-Videsater, Bjorkhem-Bergman et al. 2004)

SILIBININ
Silibinin (also called silybin) is an important active compound found in silymarin, extracted from blessed milk thistle (Silybum marianum) which is a member of the sunflower family (Compositae).

» Silymarin: Typical dosages range from 100 mg to 900 mg daily. An example of a good product is one containing 900 mg, standardized to 80% silymarin (720 mg), 30% Silibinin (270 mg), and 4.5% Isosilybin B complex (40.5mg). Silibinin is the most biologically active constituent found in silymarin and Isosilybin B complex is the most efficient constituent of silymarin in maintaining healthy cell division.

An animal study observed the effects of combined treatment with Silibinin and doxorubicin in mice with non-small cell lung cancer. Silibinin enhanced the treatment effect of doxorubicin. The tumor weight was decreased 76% in mice with combined treatment, and only 61% in mice treated with doxorubicin alone. The combined treatment prevented weight loss that otherwise occurred in mice treated with doxorubicin alone. Microvessel density was inhibited by doxorubicin by 58% whereas in combination treatment, microvessel density inhibition was enhanced significantly to 70%. Microvessel density inhibition means that there is less blood supply to the tumor and this leads to better treatment outcomes. The inhibition of the NF-kappaB pathway was found to play a role in the synergistic combination. (Singh, Mallikarjuna et al. 2004)

VITAMIN D
In human non-small cell lung carcinoma cells, vitamin D compounds decreased the IC50 of doxorubicin in a laboratory study (IC50 is the concentration of drug needed to achieve 50% reduction in cancer cell growth). This means that when vitamin D was added, less doxorubicin was needed to achieve the same anti-tumor effect as doxorubicin alone. (Pelczynska, Wietrzyk et al. 2005)

Epirubicin (Ellence)

MULTI-COMPOUND REGIMEN
A phase II clinical trial using a combination regimen including cisplatin, epirubicin, medroxyprogesterone acetate (a hormonal drug that is a progestin derived from the naturally occurring female hormone, progesterone), recombinant IL-2, alpha-lipoic acid (300mg per day), and N-acetyl cysteine (1.8 g per day) enrolled 33 non-small cell lung cancer patients: 26 with stage IIIB disease and 7 with stage IV disease. Of thirty patients whose results could be measured, the median overall survival was 15 months. The one year survival was 55.8%. The median progression free survival was 10 months. Neutropenia was the most significant symptom of toxicity from treatment, but other toxicities were minimal. (Mantovani, Maccio et al. 2002)

Etoposide (Toposar , Etopophos, VePesid)

MELATONIN
Twenty previously untreated patients with inoperable small cell and non-small cell lung cancer were randomized in a double blind study to receive either chemotherapy alone or chemotherapy in combination with melatonin (40 mg per day). Chemotherapy consisted of carboplatin and etoposide. The trial investigated the potential of melatonin to protect against chemotherapy-induced toxicity to the bone marrow, where blood cells are produced. There was no significant difference between the groups in blood counts. (Ghielmini, Pagani et al. 1999)

Researchers from Italy published a study last year about nonsmall cell lung cancer patients receiving cisplatin and etoposide (58 patients) or cisplatin and gemcitabine (16 patients) with or without melatonin (20 mg per day). The response rate to treatment and disease control was higher in patients treated with chemotherapy and melatonin than in patients treated with chemotherapy alone. This difference was only significant in the patients receiving cisplatin and etoposide but was not significant in the group of patients receiving cisplatin and gemcitabine. (Lissoni 2007)

In a second trial from Italy, 100 metastatic non-small cell lung cancer patients were given cisplatin and etoposide with or without melatonin (20 mg per day). The patients treated with chemotherapy and melatonin had significantly less progressive disease, had better overall tumor regression, and higher 5-year survival. Three patients in the melatonin group were alive at five years after beginning treatment with chemotherapy whereas no patients were alive after two years in the chemotherapy only group. Treatment with melatonin also significantly decreased neurotoxicity, thrombocytopenia, weight loss, and asthenia. No difference was observed in alopecia and anemia. (Lissoni, Chilelli et al. 2003)

A third trial from Italy enrolled 104 metastatic non-small cell lung cancer patients who received chemotherapy treatment that consisted of cisplatin and etoposide or gemcitabine alone. Patients were randomized to receive chemotherapy alone or chemotherapy and melatonin at 20 mg per day. The response rate to chemotherapy was higher in patients treated with melatonin, although this difference was only significant in patients receiving cisplatin and etoposide but not gemcitabine. Nevertheless, one year survival was significantly higher in the patients receiving melatonin in both chemotherapy groups. (Lissoni, Barni et al. 1999)

5-METHOXYTRYPTAMINE (5-MTT)
One hundred advanced non-small cell lung cancer patients were enrolled in a trial from Italy published last year who received either chemotherapy (cisplatin and etoposide) alone or with melatonin (20 mg per day) or 5-MTT (1 mg per day). The overall response rate and disease control was significantly higher in both the melatonin and 5-MTT groups. The chemotherapy-related toxicity such as thrombocytopenia, neurotoxicity, and asthenia was significantly reduced in patients receiving chemotherapy and melatonin or 5-MTT. 5-MTT was better than melatonin at preventing anorexia. Therefore, the much lower dose of 5-MTT was as effective as melatonin in the treatment of non-small cell lung cancer. (Lissoni 2007)

In another study, 20 metastatic lung cancer patients were treated with cisplatin and etoposide and were randomized to either receive 5-MTT (1 mg per day) in addition to chemotherapy or to receive chemotherapy treatment alone. The patients treated with chemotherapy and 5-MTT had significantly reduced anemia and significantly less progressive disease in comparison to the patients treated with chemotherapy alone. (Lissoni, Malugani et al. 2003)

Gemcitabine (Gemzar)

MELATONIN
Researchers from Italy published a study last year about non-small cell lung cancer patients receiving cisplatin and etoposide (58 patients) or cisplatin and gemcitabine (16 patients) with or without melatonin (20 mg per day). The response rate to treatment and disease control was higher in patients treated with chemotherapy and melatonin than in patients treated with chemotherapy alone. This difference was only significant in the patients receiving cisplatin and etoposide but was not significant in the group of patients receiving cisplatin and gemcitabine. (Lissoni 2007)

A second trial from Italy enrolled 104 metastatic nonsmall cell lung cancer patients who received chemotherapy treatment that consisted of cisplatin and etoposide or gemcitabine alone. Patients were randomized to receive chemotherapy alone or chemotherapy and melatonin at 20 mg per day. The response rate to chemotherapy was higher in patients treated with melatonin, although this difference was only significant in patients receiving cisplatin and etoposide but not gemcitabine. Nevertheless, one year survival was significantly higher in the patients receiving melatonin in both chemotherapy groups. (Lissoni, Barni et al. 1999)

Interleukin-2, Aldesleukin (Proleukin)

MELATONIN
Twenty-five lung cancer patients received either melatonin alone, melatonin and interleukin-2, or interleukin-2 alone. Patients treated with melatonin and interleukin-2 did not experience thrombocytopenia and their platelet number was significantly higher than patients receiving interleukin-2 alone, several of whom developed thrombocytopenia. (Bregani, Lissoni et al. 1995)

MULTI-COMPOUND REGIMEN
A phase II clinical trial using a combination regimen including cisplatin, epirubicin, medroxyprogesterone acetate (a hormonal drug that is a progestin derived from the naturally occurring female hormone, progesterone), recombinant IL-2, alpha-lipoic acid (300 mg per day), and N-acetyl cysteine (1.8 g per day) enrolled 33 non-small cell lung cancer patients: 26 with stage IIIB disease, and 7 with stage IV. Of thirty patients whose results could be measured, the median overall survival was 15 months. The one year survival was 55.8%. The median progression free survival was 10 months. Neutropenia was the most significant symptom of toxicity from treatment, other toxicity was low. (Mantovani, Maccio et al. 2002)

Mitomycin C & 5-Fluorouracil

VITAMIN C (ASCORBIC ACID)
In Lewis lung cancer-bearing mice, administering ascorbic acid at 1000 mg per kg twice a week together with mitomycin C and 5-fluorouracilonce once per week was more effective than treatment with mitomycin C and 5-fluorouracil alone. (Nakano, Fujimoto et al. 1988)

COMBINATIONS TO AVOID:
N-ACETYL CYSTEINE, MELATONIN, OR RUTIN
Rutin is a flavonoid obtained from many sources, such as from buckwheat and the buds of the Chinese herb Saphora japonica. It is also found in propolis.

In a laboratory study, mitomycin C-induced small cell lung cancer cell death was inhibited by N-acetylcysteine, melatonin, and rutin. (Lee, Park et al. 2004)

Paclitaxel (Taxol, Onxol, Abraxane)

HYALURONIC ACID
Hyaluronic acid is produced naturally in the body. It is important for healthy joints and skin.

» Hyaluronic Acid: A typical dose is 100 mg and it is often combined with other supplements for joint or skin health, so it is important to read all the ingredients on the label.

Hyaluronic acid in combination with paclitaxel provides an antimetastatic effect in mice with Lewis lung cancer. Paclitaxel alone did not result in inhibition of metastasis as a negative 0.9% inhibition was achieved with paclitaxel alone. However, when hyaluronic acid was added to paclitaxel, a positive 36.3% inhibition of metastasis was achieved. (Yin, Ge et al. 2006)

MULTI-COMPOUND REGIMEN
In a human lung squamous cell carcinoma cell line, the antioxidant mixture of vitamin C, vitamin E, and beta-carotene enhanced the treatment effect of paclitaxel and carboplatin. Paclitaxel followed by carboplatin 24 hours later led to an apoptosis (cancer cell killing) rate of 54%. In contrast, the vitamins administered together with paclitaxel and 24 hours later by carboplatin led to a 70% apoptosis rate. This effect was further enhanced to an 89% apoptosis rate by pretreatment with the vitamins 24 hours before paclitaxel, then followed another 24 hours later by carboplatin. (Pathak, Singh et al. 2002)

In a follow up human trial, the same combination of chemotherapy and antioxidants was tested in 136 previously untreated patients with advanced stage IIIB and IV non-small cell lung cancer. Patients were randomized to receive chemotherapy alone (paclitaxel and carboplatin) or chemotherapy in combination with ascorbic acid 6100 mg per day, dl-alpha-tocopherol (vitamin E) 1050 mg per day, and beta-carotene 60 mg per day. The response (tumor size reduction) rate in the chemotherapy-only group was 33%, while in the combination group it was 37%. The overall survival in the chemotherapy group was 9 months and for the combination group was 11 months. Toxicity was similar between the two groups. Although the difference in effectiveness was not statistically significant, it may nevertheless still be clinically significant, offering a modest improvement in treatment response and survival. Furthermore, the result of this study does not support the concern that these antioxidants compromise the efficacy of paclitaxel-carboplatin combination chemotherapy. (Pathak, Bhutani et al. 2005)

RESERVATROL
Resveratrol is an antioxidant that can be derived from the red pigment of grape skins.

» Resveratrol: Typical doses range from 25 to 250 mg per day.

A laboratory study used three different lung cancer cell lines including lung epithelial carcinoma, non-small cell lung cancer, and giant cell carcinoma of the lung. Pretreatment of cells with resveratrol resulted in significant increase in the treatment effect of paclitaxel. However, simultaneous treatment of resveratrol and paclitaxel did not result in significant change in treatment effect. (Kubota, Uemura et al. 2003)

SELENIUM
Selenium in combination with doxorubicin or paclitaxel enhanced the chemotherapeutic effect of doxorubicin and paclitaxel in human squamous lung cancer cells in a laboratory study. (Vadgama, Wu et al. 2000)

COMBINATIONS TO AVOID:
N-ACETYL CYSTEINE AND GLUTATHIONE
Glutathione is an natural antioxidant produced in the body. Nacetylcysteine and glutathione were found to increase paclitaxel IC50 by four fold in a laboratory study using lung cancer cells. This means that when N-acetylcysteine and glutathione were added, the concentration of paclitaxel had to be four times greater to achieve the same effect as paclitaxel alone. The animal study included in the same paper found that supplementing with N-acetylcysteine in mice with induced lung cancer negated the anticancer treatment effect of paclitaxel. (Alexandre, Batteux et al. 2006)

Vincristine (Oncovin, Vincasar)

VITAMIN C (ASCORBIC ACID)
Two studies found that treatment with L-ascorbic acid of nonsmall cell lung cancer cells that had developed resistance to vincristine increased drug uptake, and partially reversed vincristine resistance. In a study from 1995, the multi-drug resistance inhibitor drug called verapamil had no added effect. (Song, Yang et al. 1995) (Chiang, Song et al. 1994)

Vinorelbine (Navelbine)

CURCUMIN
In a laboratory study, vinorelbine alone caused 37.9% cell death in non-small cell lung cancer cells. However, when pretreated with curcumin 24 hours prior to vinorelbine, the cell death rose to 61.3%, dramatically increasing the treatment effect of vinorelbine. (Sen, Sharma et al. 2005)

PHOSPHATIDYLSERINE
Phosphatidylserine is a phospholipid found in fish, green leafy vegetables, soybeans, and rice and is essential for neural cell membranes. It is best known for use to increase memory.

» Phosphatidylserine: Typical dosages range from 50 to 300 mg per day.

In a laboratory study, combined treatment with vinorelbine and phosphatidylserine significantly delayed growth of non-small cell lung cancer compared to vinorelbine given alone. In an animal study reported in the same paper, adding phosphatidylserine increased growth reduction of tumors by 59% compared to 47% with vinorelbine treatment alone. This effect was dramatically increased to 73% tumor reduction when a unique formulation was created with vinorelbine encapsulated by phosphatidylserine. (Webb, Johnstone et al. 2007)

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WHAT ABOUT LUNG CANCER AND BETA-CAROTENE?

A few studies are specifically worth mentioning here, even though they are not about combining chemotherapy and antioxidants in lung cancer patients: Two large clinical trials testing the ability of synthetic betacarotene to prevent lung cancer and a large cohort study at the Mayo Clinic of vitamin and mineral use in lung cancer patients.

In the two beta-carotene studies, researchers found that supplementing with synthetic beta-carotene resulted in increased risk for developing lung cancer. (Omenn, Goodman et al. 1994) There are two mechanisms that may explain this alarming finding: First, the high-dose synthetic beta-carotene used in these studies may have functioned more as a pro-oxidant and in both studies a high proportion of patients were smokers that had been exposed to asbestos. Second, beta-carotene at high dosages may cause a decrease in other protective carotenes, which may already be low in smokers and people exposed to asbestos. Therefore, high dose betacarotene supplementation is not advised in smokers or those who have been exposed to asbestos. Additionally, when considering the use of beta-carotene, a natural form is preferable to the synthetic form.

In the large cohort study from the Mayo Clinic, researchers analyzed self-selected vitamin and mineral use in 1,129 non-small cell lung cancer patients receiving appropriate medical treatment. They found that median survival was 4.3 years in vitamin and mineral users, verses 2 years for non-users. After adjustment for confounding factors, a significant survival advantage remained. In addition, vitamin and mineral users had better quality of life as measured by the Lung Cancer Symptom Scale (LCSS). (Jatoi, Williams et al. 2005) A second, smaller cohort study from the the Mayo Clinic with 178 small cell lung cancer patients, treated as appropriate, found that there was a smaller but still statistically significant survival advantage in vitamin and mineral users, but no improvement in quality of life. (Jatoi, Williams et al. 2005)
Jatoi, A., B. Williams, et al. (2005). “Is voluntary vitamin and mineral supplementation
associated with better outcome in non-small cell lung cancer patients? Results from
the Mayo Clinic lung cancer cohort.” Lung Cancer 49(1): 77-84.

Jatoi, A., B. A. Williams, et al. (2005). “Exploring vitamin and mineral supplementation
and purported clinical effects in patients with small cell lung cancer: results from the
Mayo Clinic lung cancer cohort.” Nutr Cancer 51(1): 7-12.

Omenn, G. S., G. Goodman, et al. (1994). “The beta-carotene and retinol efficacy trial
(CARET ) for chemoprevention of lung cancer in high risk populations: smokers and
asbestos-exposed workers.” Cancer Res 54(7 Suppl): 2038s-2043s.

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REFERENCES

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Alexandre, J., F. Batteux, et al. (2006). “Accumulation of hydrogen peroxide is an early and crucial step for paclitaxel-induced cancer cell death both in vitro and in vivo.” Int J Cancer 119(1): 41-8.

Armas, L. A., B. W. Hollis, et al. (2004). “Vitamin D2 is much less effective than vitamin D3 in humans.” J Clin Endocrinol Metab 89(11): 5387-91.

Boik, J. (2001). Natural Compounds in Cancer Therapy. Princeton, Oregon Medical Press.

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Bregani, E. R., P. Lissoni, et al. (1995). “Prevention of interleukin-2-induced thrombocytopenia during the immunotherapy of cancer by a concomitant administration of the pineal hormone melatonin.” Recenti Prog Med 86(6): 231-3.

Chiang, C. D., E. J. Song, et al. (1994). “Ascorbic acid increases drug accumulation and reverses vincristine resistance of human non-small-cell lung-cancer cells.” Biochem J 301 (Pt 3): 759-64.

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Currently, chemotherapy is a vital part of allopathic breast cancer treatment, for both primary and metastatic disease. As advances in chemotherapy are thoroughly covered in other publications, I will instead focus on non-chemotherapy advances in this article.

This year, I have seen new research giving us more information about which herbs, supplements, and other alternative/complementary approaches can minimize treatment side effects and possibly even reduce the risk of breast cancer recurrence. Other progress has improved our ability to determine the full extent of a primary breast cancer, making possible better surgical planning. Finally, I have seen broader acceptance of tests allowing women less likely to benefit from chemotherapy to forgo it with confidence.

ANTIOXIDANTS & CHEMOTHERAPY
An excellent article by Dr. Keith Block reviewed 845 studies, discarding all those that were not randomized or controlled.1 The remaining 19 studies showed that antioxidants such as glutathione, melatonin, vitamin A, vitamin E, vitamin C, ellagic acid (from raspberries, strawberries, and cranberries), and N-acetyl cysteine did not adversely affect the outcome of patients who were also on chemotherapy. In fact, these patients had improvements in their survival time, tumor responses, or both.

As more highquality studies are published, I hope to see more oncologists using antioxidants with chemotherapy.

BOSWELLIA USE IN BRAIN METASTASES
Last year, Dr. Dana Flavin at the Foundation for Collaborative Medicine and Research in Greenwich, CT, reported on a remarkable case of a woman with breast cancer whose multiple brain metastases showed no improvement after two weeks of Xeloda and brain radiation.2 She was then started on boswellia 800 mg three times a day. (Boswellia, also known as Indian frankincense, is an herbal supplement with anti-inflammatory properties and is generally available through retail and online health food stores.) Ten weeks later, a repeat brain CT showed complete resolution of the brain metastases. Impressively, she has been maintained on boswellia for the past four years with no recurrent brain metastasis.

Subsequently, Dr. Flavin has had two more women with brain metastases greatly improve using the same regimen. Reportedly, Harvard’s Dana Farber Cancer Center is seeking approval for a clinical trial to study boswellia use in this setting.

NUTRITION CONTROVERSIES
The December 2006 San Antonio Breast Cancer Symposium (SABCS) saw the unveiling of the Women’s Intervention Nutrition Study (WINS), a large randomized, controlled trial that compared breast cancer patients on high-fat and low-fat diets.3 This study was a joint effort by several institutions including Beth Israel Deaconess Hospital, Memorial Sloan-Kettering Cancer Center, and the University of California, Los Angeles. They found a substantial survival benefit in the low-fat group, especially for those with estrogen receptor-negative cancer.

In contrast, the Women’s Healthy Eating and Living (WHEL) study published recently by the University of California at San Diego showed no survival advantage of a high vegetable/fruit, low-fat, and high-fiber diet.4 Although this trial was also large, randomized, and controlled, it had two key differences from WINS: first, the low-fat group in the WHEL study had, on average, a much higher daily fat intake than those in WINS (45 grams versus 33 grams). Second, the women in the WHEL study gained weight as opposed to those in WINS who shed pounds. Since a Mayo Clinic study showed that breast cancer survivors who gain weight have reduced survival, it is quite possible that whatever benefit the WHEL participants derived from the relatively low-fat and high vegetable/fruit intake was neutralized by their weight gain.5

Interestingly, the same group who published the WHEL study joined Stanford, the Northern California Kaiser Permanente group, and others in a large multi-institutional clinical trial. They found that when women with breast cancer combine higher vegetable-fruit consumption with increased physical activity, their chances of surviving increased by nearly 50%, regardless of their level of obesity.6

PSYCHOSPIRITUAL ASPECT OF BREAST CANCER
An interesting study out of Baylor College of Medicine noted that women who blamed themselves for their breast cancer and lacked self-forgiveness reported more mood disturbances and a lower quality of life.7

Another report in the Journal of the National Cancer Institute showed that breast cancer survivors, particularly African-Americans, have a higher rate of suicide than the rest of the population.8

These studies point to the importance of psychological health and reinforce the fact that a proactive approach to emotional issues is a key part of an integrative breast cancer treatment program.

ALTERNATIVE APPROACHES
There are various alternative approaches that have shown to be beneficial in recent studies:

» Aromatherapy massage was shown to reduce anxiety and depression.9
» Yoga improved sleep, physical function, and possibly also fatigue in women getting radiation therapy.10
» Reiki, an energy-based healing system from Japan, improved fatigue in cancer patients.11
» Mayo Clinic research suggests that American ginseng at 1000 to 2000 mg per day may be effective for alleviating cancer-related fatigue.12
» A Columbia University study showed that acupuncture can reduce the joint pains caused by aromatase inhibitors such as Femara and Arimidex.13
» Eight weeks of aerobic exercise was shown to improve depression and fatigue as well as improve physical conditioning in breast cancer survivors.14
» I was intrigued by Duke University’s report that women taking calcium supplements had more hot flashes that those who did not. This small study was presented at the ACSO Breast Cancer Symposium two weeks ago. It remains to be seen whether this relationship holds up under larger, more rigorous studies.15

BREAST MRI
Breast MRI continues to be an area of active research. It is well documented that up to 15% of breast cancers are missed by mammogram and breast ultrasound.16 MRI will catch most of these.

Despite this obvious advantage, MRI is not yet ready to replace mammography as our standard screening tool as it does have a significant false-positive rate. In other words, it is very good at finding even tiny breast lumps, but it cannot always distinguish a benign lump from a malignant one.

Nevertheless, one group of women were found to be excellent candidates for MRI breast screening: those with a high risk of developing breast cancer within five years. Women with BRCA gene mutations fall into this category. In addition, women who have a 20% or greater lifetime risk of breast cancer also fall into this group. One easy way to estimate one’s risk is to use the Gail risk model, an interactive computer program where inputting specific information such as age and family history of breast cancer yields an estimate of both 5-year and lifetime risk of breast cancer. It can be accessed at the National Cancer Institute website: www.cancer.gov/bcrisktool.

For those who have already been diagnosed with breast cancer, a breast MRI can add to the information provided by the mammogram to help plan a surgery that will be sure to remove all of the cancer. In fact, researchers have shown that in at least 16% of women, a preoperative MRI found a second cancer that the mammogram had missed and that would probably have escaped the planned lumpectomy.17 In another study, MRI findings resulted in a change in surgical plans in 15% to 30% of cases.18,19

Additionally, a small study from New York University was just presented at the ASCO Breast Cancer Symposium, showing that women who had preoperative MRI not only tended to have a lower rate of re-excision and improved surgical margins, but also had fewer mastectomies.20  I am now beginning to see breast surgeons who routinely incorporate MRI in their pre-operative protocol.

Unfortunately, this research is not mature enough to say definitively whether preoperative breast MRI is beneficial.  In the meantime, those women who would rather risk a negative (i.e. unnecessary) biopsy than a potentially incompletely excised cancer should talk to their breast surgeons about an MRI.

It is important to note that there are currently no national standards for breast MRI imaging as there are for mammograms. Therefore, it makes sense to have your MRI done at a center that uses dedicated breast MRI coils and whose radiologists have at least three years of experience interpreting them.

GENE EXPRESSION PROFILING
I am very happy to report steady advances in the realm of personalized treatment. For many years, women with lymph node-negative, early stage breast cancer were encouraged to undergo chemotherapy even though only 2% of those over 50 years of age, and only 7% of those under 50, would be expected to benefit from it.21 (Although the percentage of women with early stage breast cancer being saved by chemotherapy seems small, when multiplied by the hundreds of thousands of women diagnosed, it actually translates into thousands more women surviving their breast cancer each year.) The problem is that you have to give chemotherapy to many, many women in order to save one. For example, for every 100 women over 50 being treated, 98 would get chemotherapy, with all its side effects but none of its benefit, in order to save two women.

This situation changed dramatically in 2003 when a company called Genomic Health burst on the scene with an elegant test to help decide who would benefit from chemotherapy. They examined DNA from thousands of breast cancer samples from women whose ultimate response (relapse or no relapse) to tamoxifen was known. They found 21 genes that accurately predicted whether a woman with hormone-positive breast cancer taking anti-estrogen therapy would relapse over the next 10 years. The result is OncoType DX, a gene expression profiling test that has now allowed many women to forgo chemotherapy with confidence.

Agendia is another biotech company whose gene profiling test was approved by the FDA this year. Called MammaPrint, it uses a 70-gene profile and has been shown to be as accurate as the Oncotype DX test in predicting breast cancer relapse.

There are differences between the two tests. Oncotype DX requires the breast cancer be lymph node-negative, early stage, and hormone receptor-positive. It can use preserved breast cancer specimens, so even if the cancer was removed years ago, the test can still be done on that tissue sample (pathologists always save tissue specimens). The MammaPrint test requires women to be early stage and lymph node-negative but does not require them to be hormone receptor-positive. However, it does require a fresh tissue sample taken at the time of surgery.

Surprisingly, many oncologists still choose not to discuss these exciting new tests with their patients.

TUMOR MARKERS
A blood test that accurately tracks metastatic cancer activity is a holy grail of sorts in the breast cancer diagnostic world. Armed with the results of this test, one can monitor the effectiveness of the current treatment regimen more quickly. Such a test, called a tumor marker, certainly has advantages over CT, MRI, and PET scans in that it can be done more frequently and without exposure to radiation.

For many years, the only choices were blood tests for CA 15.3 or CA 27.29. Unfortunately, these tumor markers were useful only for some women.

Recently, a new blood test has become available that looks for cancer cells, called circulating tumor cells, in the bloodstream. This test, called Cell Search, uses monoclonal antibodies to find as few as one cancer cell per billion normal cells in a small sample of blood.22 The FDA has approved this test only for women with metastatic breast cancer. It is available from Quest Diagnostics and many other laboratories.

Women with metastatic HER2-positive breast cancer now also have a more accurate tumor marker. Monitoring the HER-2 ECD blood test over time has proved very useful in this regard as noted by several research papers presented at the San Antonio Breast Cancer Symposium (SABCS) and the American Society for Clinical Oncology annual conference (ASCO).23,24 This FDA approved test may be obtained through Specialty Laboratories.

CELEBREX FOR METASTATIC BREAST CANCER
Last year, a group of French researchers published the results of a well-designed study looking at a new drug combination for treating breast cancer.25 They used Celebrex, a COX-2 inhibiting anti-inflammatory medication, and Aromasin, an anti-estrogen drug. This combination was prescribed as the first-line treatment for metastatic breast cancer and was compared to using Aromasin alone. The Celebrex plus Aromasin group had 75% more women whose cancer went into complete or partial remission than did those who took Aromasin alone.

Interestingly, women who took Celebrex plus Aromasin had significantly less pain, joint aches, fatigue, and insomnia. But more of these women experienced edema (about 8% versus 2% in the Aromasin alone group) and hypersensitivity reactions. In fact, anyone who is allergic to Sulfa should not take Celebrex, but should take another COX-2 inhibiting anti-inflammatory agent instead.

Although this study was done with Aromasin, other aromatase-inhibiting anti-estrogens such as Femara and Arimidex may very well work with Celebrex in the same way.

ER-NEGATIVE BREAST CANCER MAY RESPOND TO ANTI-ESTROGEN THERAPY AFTER ALL
At the December San Antonio Breast Cancer Symposium, much excitement surrounded a multinational study of the effect of aromatase inhibitors on estrogen receptor-negative breast cancer.26 In short, they tested the truism that estrogen receptor-negative cancers do not respond to anti-estrogen therapy.

This elegant study gathered the initial breast cancer samples of 116 women and noted their estrogen receptor status. Some had their cancers progress and, despite being estrogen-negative, were treated with aromatase-inhibiting anti-estrogens. It turned out that a notable 18% of these women had their cancer shrink when they took either Femara or Arimidex.

These results may mean that currently accepted methods do not always detect estrogen receptor-positivity accurately enough. In fact, recent research shows that looking for estrogen-related genes is a much more accurate way of determining estrogen receptor status than the current standard that relies on estrogen receptor dyes.27

The bottom line: when a post-menopausal estrogen receptor-negative cancer is resistant to standard treatment, it makes sense to consider trying Femara or Arimidex.

HER-2 POSITIVE METASTATIC BREAST CANCER
A recent flurry of studies have shown that women whose cancers grew while on Herceptin but continued the Herceptin treatment anyway, lived up to twice as long as those who did not.28,29,30,31

CURRENT HER-2 TESTING PROTOCOLS MAY BE INADEQUATE
A well-respected breast cancer research group called the National Surgical Adjuvant Breast and Bowel Project caused a stir at the ASCO meeting this year. They showed that the IHC and FISH protocols currently used for determining HER-2 status do not predict which women will respond to Herceptin.32 In fact, women who were IHC 2+ or less, or who were FISH-negative but received Herceptin anyway, had a 50% to 80% lower breast cancer recurrence rate than those who did not receive it.

Of course, the top researchers in the breast cancer treatment world, including the authors of this study, hastened to say that this is a preliminary study and oncologists should not be giving Herceptin to women unless they are FISH-positive or IHC 3+ positive for HER-2. While this may be sound public health policy, in an individual case that is resistant to standard treatment, it makes sense to consider trying Herceptin if it has not been tried yet.

In a related study, Italian researchers gave Herceptin to women whose cancers were HER-2 negative according to the standard protocol but were found to have the HER-2 protein in their blood (according to the serum HER ECD blood test).33 These women had more cancer shrinkage when given Herceptin than those who did not receive Herceptin.

HELP FOR “CHEMOBRAIN”
Provigil improved memory and attention in a randomized, controlled trial of women who had chemotherapy for their breast cancer. Of note, scientists from Cephalon, the pharmaceutical company that manufactures Provigil, participated in this study.34

ON THE HORIZON
I am optimistic about the continued advancement of cancer vaccines. The underlying science has been more difficult to conquer than many had envisioned. Nevertheless, the latest round of vaccines in clinical trials has shown some promise.

Vaccines for HER-2 Positive Breast Cancer
Every year sees more anti-HER-2 vaccines introduced into clinical trials. Currently, there are at least five such vaccines being tested. A particularly promising one, E75, was given to women who were at high risk for cancer relapse after receiving the standard treatment.35 There were about 60% fewer relapses at two years compared with those who did not receive E75. A Phase III trial is currently in the planning stage.

Vaccines for Metastatic Breast Cancer (HER-2 Positive and Negative)
The National Cancer Institute presented its latest data on PANVAC at the ASCO Breast Cancer Symposium. PANVAC is a fascinating vaccine that uses a virus to deliver potent immune-activating substances directly to the cancer site. It is hoped that PANVAC will mobilize the immune system to seek out and destroy every breast cancer cell in a woman’s body. While it showed some activity when used as a single agent, the recent NCI study using it in combination with the chemotherapy agent Taxotere showed promising prolonged partial remissions in the two patients who have tried it so far.37

Crying for Better Breast Cancer Screening
The most paradigm-shifting research presented at the ASCO Breast Cancer Symposium was a small study that analyzed the tears of women with breast lumps using a special machine called a mass spectrometer.38 They were able to tell who had breast cancer and who did not based on the results of a protein “fingerprint” of the tears. If these results are corroborated in further research, women may eventually be able to say goodbye to their annual mammogram.

Antiviral Therapy for Metstatic Breast Cancer
In recent years, there is accumulating evidence of a strong link between the human mammary tumor virus and the occurrence of breast cancer. Researchers at the National Cancer Institute are testing this hypothesis. They showed that nelfinavir (Viracept), a protease-inhibiting antiviral drug commonly prescribed for HIV, caused breast cancer cells to die in laboratory conditions.39 I hope it will not be long before a human clinical trial is done to answer this important question more conclusively.

Gwendolyn Stritter, MD, is a clinical advocate for those with difficult or life-threatening health problems. Her practice is focused especially on those with breast cancer. She is a member of the American Society of Breast Disease, the Society for Integrative Oncology, the American Society of Clinical Oncology, and the American Pain Society. Dr. Stritter would like to thank Michael McCulloch and Autumn Stanley for their editorial assistance. She would also like to thank Carl Stritter and Ann Baldwin for reviewing the manuscript. Visit her online at www.strittermed.org.

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39. Gills JJ et al. Clin Cancer Res. 2007 Sep 1;13(17):5183-94

Scientific evidence suggests that combining certain chemotherapy treatments with certain antioxidants at specific dosages can help improve drug effectiveness or reduce the severity of side effects.

This issue is important because it has long been the opinion of many practicing oncologists that antioxidants should simply not be used concurrently with chemotherapy because it was believed that the combination might inhibit chemotherapy effectiveness. This reluctance stems, in part, from the fact that some chemotherapy drugs work by strongly promoting oxidation. This is especially the case for the class of chemotherapy drugs called anthracyclines (Adriamycin and epirubicin), the alkylating agents (chlorambucil, cyclophosphamide, thiotepa, and busulfan) and the platinum drugs (cisplatin and carboplatin). Antioxidants, by definition, inhibit oxidation, so it was believed that antioxidants would prevent these chemotherapy drugs from working properly.

Chemotherapy drugs that cause high levels of oxidative stress are thought to rely, in part, on using this stress mechanism to kill cancer cells. But oxidative stress might actually reduce the overall effectiveness of chemotherapy. Oxidative stress slows the process of cell replication, but it is during cell replication that chemotherapy actually kills cancer cells (Conklin, 2004), so slower cell replication can mean lower effectiveness of chemotherapy. One approach to addressing this problem is the addition of certain antioxidants at specific dosages to lessen oxidative stress, thus making the chemotherapy treatment more effective (Perumal and Shanthi, 2005).

The interaction between chemotherapy and antioxidants is more complex than simply promoting and inhibiting oxidative stress, however. There are several mechanisms by which chemotherapy functions and antioxidants also have a number of different effects on the body. Each antioxidant has a different interaction with chemotherapy and this effect can even change based upon the dosage used.

Today, the question may in fact not be whether antioxidants should be used in combination with chemotherapy but rather which should be used and at what dosages.

In this evidence-based review article, we discuss the results of current research showing how antioxidants may enhance or, in some cases, inhibit the therapeutic action of specific chemotherapy drugs used in the treatment of breast cancer. Some of these antioxidants may also reduce chemotherapy side effects or inhibit chemotherapy resistance in breast cancer cells. Finally, some of these antioxidants have been found to be useful for restoring the natural antioxidants in the body, which are often depleted after the completion of chemotherapy.

We searched for clinical or laboratory data published in peer-reviewed medical journals, conducted by cancer researchers in universities and medical research facilities around the world, from MD Anderson Cancer Center in Houston to Peking University in Beijing and dozens of institutions in between. These studies were published in prestigious, peer-reviewed journals such as Anticancer Research, Breast Cancer Research and Treatment, and the Journal of the National Cancer Institute. Some of these studies are still in early stages and include only laboratory data, while others have advanced to include animal or human patients.

We then organized all this data into the major categories of specific chemotherapy drugs. Within each section for a specific drug are found the research on combinations of that drug with various antioxidants, grouped by the name of the antioxidant in question and then by alphabetical order. We also point out specifically which studies were conducted in a laboratory (i.e. using cancer cell cultures), which were conducted using animals, and which were conducted with human volunteers. The dosages given are not necessarily appropriate for all patients and should be individualized with practitioner guidance.

Studies On Single-agent Chemotherapy

DOXORUBICIN/ADRIAMYCIN IN COMBINATION WITH ANTIOXIDANTS

Biochanin A & Silymarin
Biochanin A is a flavonoid found in legumes (the family leguminaceae) and in red clover (Trifolium pratense). Silymarin is extracted from the blessed milk thistle plant (Silybum marianum) which is a member of the sunflower family (Compositae). A laboratory study found that estrogen receptor-positive and multidrug-resistant breast cancer cells that are P-glycoprotein positive became more sensitive to Adriamycin treatment when treated in combination with biochanin A and silymarin (Zhang and Morris, 2003). P-glycoprotein is a protein complex believed to play a role in the resistance of cancer cells to chemotherapy (Rudas and Filipits, 2003). When cancer cells become more sensitive to a chemotherapy drug this means that they can more easily be destroyed by the drug.

» Red Clover Tea (good source of Biochanin A): Typical dosage for a tea is 3 cups per day. In capsules and tablets, 2g to 4g, 3 times per day. In tincture, 2 ml to 4 ml, 3 times per day.

» Silymarin: Typical dosages range from 100 mg to 900 mg daily. An example of a good product is one containing 900 mg, standardized to 80% silymarin (720 mg), 30% silibinin (270 mg) and 4.5% isosilybin B complex (40.5 mg). Silibinin is the most biologically active constituent found in silymarin and isosilybin B complex is the most efficient constituent of silymarin in maintaining healthy cell division.

Rutin & Other Flavonoids
Flavonoids are beneficial antioxidants found in fruits and vegetables, especially red grape juice, green tea, soy, and many other legumes. One potential useful example of a beneficial flavonoid is monoHER, one of the most powerfully active antioxidants in flavonoid products, such as Venoruton, which is used to treat varicose veins (van Acker and Boven, 1997). MonoHER is a derivative of the flavonoid rutin, obtained from many sources, such as buckwheat and the buds of the Chinese herb Saphora japonica. It is also found in propolis. The ability of flavonoids to protect the integrity of blood vessels may, in part, explain how they protect the heart.

Adriamycin can cause cardiomyopathy, a disease of the heart muscle that impairs the heart’s ability to pump blood and deliver it to the rest of the body. Three studies found that flavonoids have a beneficial effect in protecting the heart against Adriamycininduced heart damage. The toxicity of Adriamycin to the heart is thought to be caused by oxidative stress. Flavonoids reduce oxidative stress, which may explain how they protect the heart. The studies, conducted in the Netherlands, found that the flavonoid monoHER almost completely protected the heart without influencing the antitumor effect of Adriamycin treatment against estrogen receptor-positive breast cancer cells (Bast and Kaiserová, 2007; Hüsken and de Jong 1995; van Acker and Boven 1997.)

» Rutin: Typical dosages range from 500 mg to 1,000 mg daily.

Genistein
Genistein is an isoflavone found in legumes, especially soybeans. Isoflavones are antioxidants that counteract the damaging effects of free radicals in body tissues.

Genistein has structural similarity to estradiol and therefore competes with estradiol for estrogen receptor binding. This blocks estradiol from stimulating cell growth (Sarkar and Adsule, 2006).

Isoflavones, such as genistein, also have antiangiogenic effects, blocking the formation of new blood vessels needed to support the growth of tumors.

Genistein sensitizes cancer cells to apoptosis induced by chemotherapeutic agents including Taxotere, gemcitabine, and cisplatin. Apoptosis is the “cellular programming” in the DNA which instructs cells to self-destruct when they have reached the end of their intended life cycle. Apoptosis is a natural and desirable part of cellular growth, and cancer cells “forget” when they are supposed to stop growing, thus contributing to uncontrolled cell growth. Some chemotherapy drugs can help induce apoptosis in cancer cells.

Genistein also directly inhibits breast cancer cell growth both in cell culture and animals (Sarkar & Adsule, 2006).

A laboratory study from Japan showed genistein made estrogen receptor-negative breast cancer cells more responsive to Adriamycin treatment, thus increasing effectiveness. In contrast, no effect or even decreased drug effectiveness was noted in estrogen receptor-positive breast cancer cells (Lim and Kim, 2006).

Another laboratory study from Japan showed that HER2/neu-positive breast cancer cells (which contributes to malignant transformation of cancer cells) were more sensitive to treatment when the combination of genistein and Adriamycin was used (Satoh and Nishikawa, 2003). A laboratory study conducted in Italy found that genistein increases the treatment effect of Adriamycin in both estrogen receptor-positive and estrogen receptor-negative breast cancer cells. This effect was even stronger in Adriamycin resistant breast cancer cells (Monti and Sinha, 1994). When cancer cells become resistant to a chemotherapy drug, this lowers the drug’s effectiveness. An important goal of cancer research is to identify compounds which can reduce chemotherapy resistance, and thus perhaps increase chemotherapy effectiveness.

» Genistein: A good product will use organic non-GMO genistein. Typical dosages range from 40 mg to 60 mg daily. One cup of soy milk will contain on average about 45 mg of genistein and the other related isoflavones.

Glutathione
Adriamycin can cause cardiomyopathy (damage to heart muscle). This injury may happen through oxidation. In one study, dietary glutathione and Adriamycin administered to rats showed that this combination can diminish Adriamycin-induced oxidative damage to the heart muscle (Cao and Kennedy, 1999).

» Glutathione: Typical dosage ranges between 50 mg and 600 mg daily. N-acetyl cysteine is the pre-cursor of glutathione and is more efficiently absorbed. When taking Glutathione or N-acetyl cysteine, combine with three times as much vitamin C. Vitamin C prevents these amino acids from being oxidized in the body and ensures their ability to act as antioxidants.

Grape Seed Polyphenol
Grape seed polyphenol increased effectiveness of Adriamycin against estrogen receptor-positive breast cancer cells and also reversed Adriamycin resistance in an animal study from China (Zhang and Zhou, 2004).

Grape Seed extract strongly increases the treatment effect of Adriamycin in both estrogen receptor-positive and -negative breast cancer cells according to a US study (Sharma and Tyagi, 2004).

» Grape Seed Polyphenol (Grape Seed Extract): Sometimes products may combine grape seed extract with the extract called Resveratrol, the “red wine antioxidant” from the red pigment of grape skins. Typical dosages range between 50 mg and 200 mg daily.

Green Tea Polyphenols
Epigallocatechin-3-gallate (EGCG) is the principal polyphenol found in green tea.

In a laboratory study from China, it was demonstrated that green tea polyphenol improved effectiveness of Adriamycin in estrogen receptor-positive breast cancer cells that had become resistant to adriamycin treatment (Zhu and Wang, 2001).

» Green Tea Polyphenols (EGCG): One cup of green tea contains between 10 and 400 mg of polyphenols depending on the source, amount of leaves used, and time the tea steeps. EGCG may be conveniently obtained from extracts. A good product contains 725 mg, standardized to 98% polyphenols, 45% of which is EGCG.

Melatonin
Melatonin protects hematopoietic stem cells from Adriamycin treatment according to a Japanese study (Greish and Sanada, 2005). Hematopoietic stem cells produce the different components of blood, including red and white blood cells and, if damaged by chemotherapy, may lead to anemia or immune deficiency.

Also, an animal and laboratory study from Korea showed that the addition of melatonin to treatment with Adriamycin decreased mortality in rats by 20%. This treatment also reduced Adriamycin-induced side effects, such as weight loss and problems with the blood pressure or blood flow output of the heart. These researchers also found that when melatonin was given together with Adriamycin, a lower dose of chemotherapy could achieve the same efficacy as a higher dose of Adriamycin treatment alone (Kim and Kim 2005).

In an Italian study, 77 advanced breast cancer patients received chemotherapy alone or a combination of chemotherapy and melatonin. Patients treated with melatonin had significantly higher 1-year survival rates and tumor regression rates. In addition, melatonin treated patients had less thrombocytopenia. (Thrombocytopenia is a reduction in platelets, which are cells in the blood that help blood to clot. Thrombocytopenia is sometimes associated with abnormal bleeding.) Patients receiving melatonin also experienced reduced neurotoxicity (damage to the nerves including weakness or numbness, memory loss, headache, cognitive and behavioral problems and sexual dysfunction), cardiotoxicity (toxicity that effects the heart), stomatitis (inflammation of the mouth), and asthenia (loss of strength and energy). This study concluded that in advanced breast cancer patients with poor clinical status, melatonin may reduce toxicity and increase efficacy of treatment (Lissoni and Barni, 1999).

» Melatonin: Typical dosages range from 1 mg to 20 mg. If aiming for a high dosage, one should start with 1 mg and increase the dosage slowly by 1 mg every 3-7 days. The ideal is to achieve peak blood levels of melatonin at about 2am. To do so one can take the melatonin half an hour before bedtime between 9 and 10pm. For
more discussion about the healing value of sleep, click here.

Micronized Zeolite
Zeolites (from the Greek “zein,” meaning “to boil”, and “lithos,” meaning “stone”) are minerals with a porous structure. A Croatian study found that combined treatment of zeolite and Adriamycin in mice and dogs with cancer lead to a reduction in pulmonary metastasis (Zarkovic and Zarkovic, 2003).

» Micronized Zeolite: Usually this is available in a liquid form and dosages range from 5 drops twice a day to 10 drops 3 times a day.

Fish Oil Concentrate (Omega-3, EPA, & DHA)
Mice with estrogen receptor-negative breast cancer were treated with Adriamycin and fed fish oil concentrate. The control group was treated with Adriamycin and given standard food. Mice that were given food supplemented with fish oil concentrate had significantly less tumor growth than the control group (Hardman and Munoz, 2002).

In another animal study of mice with induced breast cancer, one group was given feed containing 5% corn oil and the other was given 3% fish oil concentrate and 2% corn oil. The group fed with added fish oil concentrate responded better to treatment with Adriamycin without increased toxicity (Hardman and Avula, 2001).

A third animal study from India of mice with estrogen receptor-negative breast cancer showed that the incidence of lung metastases and tumor growth rate was significantly less in mice whose diet was supplemented with fish oil concentrate versus mice fed a diet high in corn oil (Rose and Connolly, 1993). This demonstrated that the fish oil helped reduce the ability of breast cancer cells to grow, and to spread to the lungs.

» Omega 3 Polyunsaturated Fatty Acids (PUFA, from fish oil): Typical dosage range is from 1,000 mg to 10,000 mg daily.

Quercetin
Quercetin is a flavonoid found in capers, apples, tea, onions, red grapes, citrus fruits, leafy green vegetables, cherries, and raspberries. Quercetin has anti-inflammatory activity, inhibits allergic and inflammatory reactions, and has strong antioxidant activity.

An Italian laboratory study found that quercetin greatly increases the treatment effect of Adriamycin in estrogen receptor-positive Adriamycin-resistant breast cancer cells (Scambia and Ranelletti, 1994).

» Quercetin: Typical dosages range from 200 mg to 1,200 mg daily.

All-Trans Retinoic Acid (ATRA )
Retinoic acid is the acidified form of vitamin A (Retinol), the animal form of vitamin A. Retinol is a fat-soluble, antioxidant vitamin important in bone growth and vision. Retinol is ingested in a precursor form from animal foods (liver and eggs) and plants (carrots and spinach). In a laboratory study from Poland, researchers found that the antitumor activity of Adriamycin against estrogen receptor-positive breast cancer cells is increased when ATRA is added. Interestingly, the combination of ATRA and Adriamycin significantly outperformed the combination of Adriamycin and tamoxifen (Czeczuga-Semeniuk and Wo?czyski, 2004).

From Italy, a laboratory study testing estrogen receptorpositive breast cancer cells found that the combination of ATRA and Adriamycin inhibited cell growth more than either treatment alone (Toma and Maselli, 1997).

From the United States, a laboratory study found that ATRA makes estrogen receptor-positive and -negative cells more vulnerable to Adriamycin treatment (Wang and Yang, 2000).

A fourth study, from France, found that in multidrugresistant estrogen receptor-positive breast cancer cells, which are highly invasive, ATRA decreases their ability to metastasize (Affoué and Akeli, 1999). Tretinoin is the generic name and Vesanoid is one of the trade names for this prescription drug.

Selenium
Two laboratory studies demonstrated selenium enhanced the treatment effect of Adriamycin in estrogen receptor-positive breast cancer cells (Li and Zhou, 2007; Vadgama and Wu, 2000).

» Selenium (mineral): The US adult Tolerable Upper Intake Level (UL) is 400 mcg a day and the Lowest Observed Adverse Effects Level (LOAEL) for adults is about 900 mcg daily. Selenium is best used in its highly absorbable amino acid forms, such as Lselenocysteine and L-selenomethionine.

Silibinin
Silibinin (also called silybin) is an important active compound found in silymarin, extracted from blessed milk thistle (Silybum marianum). In a laboratory study from the United States, silibinin increased the ability of Adriamycin to inhibit growth of estrogen receptor-positive and -negative breast cancer cells (Tyagi and Agarwal 2004).

Silibinin potentiates the effect of Adriamycin in Adriamycin-resistant estrogen receptor-positive breast cancer cells according to a laboratory study from Italy (Scambia and De Vincenzo, 1996).

» Silymarin: Silibinin is the most biologically active constituent found in silymarin and isosilybin B complex is the most efficient constituent of silymarin in maintaining healthy cell division. Typical dosages range from 100 mg to 900 mg daily. An example of a good product is one containing 900 mg, standardized to 80% silymarin (720 mg), 30% silibinin (270 mg) and 4.5% isosilybin B complex (40.5 mg).

Topical 99% Dimethyl Sulfoxide (DMSO)
Dimethyl sulfoxide (DMSO) is a natural substance derived from wood pulp. Two patients undergoing Adriamycin treatment developed grade three palmar-plantar erythrodysesthesia syndrome (more commonly known as hand and foot syndrome). Their symptoms resolved over one to three weeks after receiving topical 99% DMSO four times daily for fourteen days (Lopez and Wallace, 1999).

» Dimethyl sulfoxide (DMSO): This product is used topically in small amounts such as 1/8 teaspoon. Thorough cleaning of the skin prior to use is essential. Drying of the skin can occur. This should be a practitioner-guided approach.

DOCETAXEL (TAXOTERE) IN COMBINATION WITH ANTIOXIDANTS

All Trans Retinoic Acid (ATRA)
ATRA increased effectiveness of Taxotere in a laboratory study when estrogen receptor-positive and -negative breast cancer cells are pretreated with ATRA three days prior to treatment with Taxotere (Wang and Wieder, 2004).

Gamma-Linolenic Acid (GLA)
According to a US study (Menendez and Ropero, 2004), the omega-6 polyunsaturated fatty acid gamma-linolenic acid (GLA) and vitamin E, used in combination, enhance the effectiveness of Taxotere in human breast cancer cells (both estrogen receptor positive and negative).

» Gamma-linolenic Acid (GLA): Available as evening primrose oil, borage seed oil, and black currant seed oil. Typical doses range from about 300 mg to 3,000 g daily, usually with meals.

Garlic
There has been concern that garlic may alter the way drugs are metabolized. In a study conducted at the National Cancer Institute, researchers found that garlic does not significantly affect the way Taxotere circulates through the body, but it may reduce the body’s ability to clear Taxotere (Cox and Low, 2006). This could potentially increase levels of the drug in the blood.

» Garlic (from the garlic plant): Typical dosage is approximately one teaspoonful of fresh garlic or 1,000 mg to 3,000 mg of a standardized extract. Note that the active ingredient, allicin, is inactivated by cooking.

Genistein
Genistein was found to sensitize cancer cells to Taxotere treatment in a laboratory study conducted in the US (Sarkar and Adsule, 2006). Another US laboratory and animal study confirmed that genistein significantly increases Taxotere’s effectiveness in estrogen receptor-negative cancer cells (Li and Ahmed, 2005).

» Genistein: A good product will use organic non-GMO genistein. Typical dosages range from 40 mg to 60 mg daily. One cup of soy milk will contain on average about 45 mg of genistein and the other related isoflavones.

Vitamin E
Palmar-plantar erythrodysesthesia (also known as hand-foot syndrome) is a painful feeling in the palms of the hands and the soles of the feet that can sometimes make the skin to turn a red or dark pink color. The skin can also develop ulcers, blisters, or sores. The chemotherapy drugs most likely to cause hand-foot syndrome are cyclophosphamide, Taxotere, Adriamycin, liposomal Adriamycin, etoposide, fluorouracil, hydroxyurea, mercaptopurine, methotrexate, mitotane, bleomycin, capecitabine, cytarabine, and thiotepa.

In a human clinical study from Turkey, five patients treated with a Taxotere and capecitabine combination developed moderately severe palmar-plantar erythrodysesthesia (hand-foot syndrome). They started vitamin E therapy at 300 mg a day (equivalent to 450 IU) without dose reduction of chemotherapy. After one week of treatment, hand-foot syndrome symptoms began to disappear (Kara and Sahin, 2006).

Note that the usual treatment for hand-foot syndrome is dose reduction of chemotherapy, which may lead to reduced effectiveness. This study is important because patients were able to continue at the therapeutic dose of chemotherapy with the help of adjunctive vitamin E.

» Vitamin E: Avoid synthetic vitamin E, such as alpha-tocopherol or succinate. Seek out the mixed tocopherols, particularly those containing the vitamin E fractions called tocotrienols and gamma-tocopherol. Typical dosage ranges from 50 IU to 800 IU daily.

PACLITAXEL/TAXOL IN COMBINATION WITH ANTIOXIDANTS

Curcumin
Curcumin is an extract of the Indian curry spice plant turmeric. It is a polyphenol and produces the yellow color of turmeric. An animal study showed that curcumin enhances the effectiveness of treatment with Taxol and also prevents lung metastasis (Aggarwal and Shishodia, 2005).

» Curcumin: The best supplements contain curcumin at 75% or higher concentration. Typical doses range from 500 mg to 4,000 mg daily. Take with meals, as they can cause stomach upset when taken on an empty stomach. Bioavailability is increased when combined with piperine, the alkaloid responsible for the pungency of black pepper.

Genistein
In a study from Taiwan, genistein (an isoflavone found in soybeans) significantly decreased the effectiveness of both Taxol and vincristine in treating estrogen receptor-positive and -negative cancer cells (Liao and Pan, 2004). It is not recommended that genistein be combined with Taxol or vincristine.

Green Tea
Epigallocatechin-3-gallate (EGCG) is the principal polyphenol found in green tea. A laboratory study from the US found that EGCG increased the sensitivity of human breast cancer cells to treatment with Taxol. It achieved this effect at concentrations that are similar to those in the blood after an oral dose of EGCG (Masuda and Suzui, 2003).

» Green Tea Extract: One cup of green tea contains between 10 and 400 mg of polyphenols depending on the source, amount of leaves used, and time the tea steeps. EGCG may be conveniently obtained from extracts. A good product contains 725 mg, standardized to 98% polyphenols, 45% of which is EGCG.

Propolis
Propolis is a resinous substance that honey bees collect from tree buds to prevent diseases in the hive. It is used in human health to protect the heart, reduce inflammation, heal skin burns, treat tooth decay and gum disease, and for its antibiotic, antiviral and antifungal properties.

In an animal study from India, the combination of Taxol and propolis protected mice against developing cancer more strongly than did treatment with either Taxol or propolis alone (Padmavathi and Senthilnathan, 2006). The researchers found that in animals given propolis, their bodies were less susceptible to oxidative damage to their fat cells, and they had an increase in activity of antioxidants.

» Propolis: Insist on propolis that is tested to avoid heavy metal content. Typical dosage range is from 100 mg to 3,000 mg daily.

All Trans Retinoic Acid (ATRA)
In a laboratory study from Canada, researchers found that ATRA sensitizes estrogen receptor positive cells to Taxol (Pratt and Niu, 2006). Tretinoin is the generic name, and Vesanoid is one of the trade names for this prescription drug.

Vitamin E
A human trial was conducted in Greece with thirty-one patients to evaluate the neuroprotective effect of vitamin E when used together with cisplatin and Taxol chemotherapy treatment. Whereas 73.3% of control patients receiving chemotherapy alone developed neurotoxicity side effects, only 25% of patients who received 600 mg (or 900 IU) per day of vitamin E in combination with chemotherapy developed neuropathy, during and up to three months after chemotherapy (Argyriou and Chroni, 2005).

» Vitamin E: Avoid synthetic vitamin E, such as alpha-tocopherol or succinate. Seek out the mixed tocopherols, particularly those containing the vitamin E fractions called tocotrienols and gamma-tocopherol. Typical dosage ranges from 50 IU to 800 IU daily.

EPIRUBICIN/ELLENCE IN COMBINATION WITH ANTIOXIDANTS

Flavonoids
In a study from Hungary, chemotherapy-resistant estrogen receptor-
negative breast cancer cells became more sensitive to treatment
with epirubicin when treated with flavonoids (Gyémánt and
Tanaka, 2005).

Superoxide Dismutase, Catalase, & Glutathione
A laboratory study from Turkey study showed that the addition of superoxide dismutase, catalase and glutathione, to estrogen receptor positive cancer cells treated with epirubicin, decreased the ability of epirubicin to kill cancer cells (Ozkan and Fiskin, 2006). It is not recommended that these antioxidants be combined with epirubicin.

Melatonin
Fourteen women with metastatic breast cancer were treated with epirubicin. Melatonin at 20 mg a day was started seven days prior to chemotherapy and continued every day through treatment. Twelve patients were evaluable after four cycles of chemotherapy. Nine out of twelve patients had normalization of platelet number and no further decline in platelet number occurred (Lissoni and Tancini, 1999).

» Melatonin: Typical dosages range from 1 mg to 20 mg. If aiming for a high dosage, one should start with 1 mg and increase the dosage slowly by 1 mg every 3-7 days. The ideal is to achieve peak blood levels of melatonin at about 2am. To do so one can take the melatonin half an hour before bedtime between 9 and 10pm.

CYCLOPHOSPHAMIDE/CYTOXAN IN COMBINATION WITH ANTIOXIDANTS

Curcumin
A US study using an animal model of human breast cancer found that supplementation with curcumin inhibited tumor regression and decreased cell death from treatment with cyclophosphamide (Somasundaram and Edmund, 2002).

Coenzyme Q10, Riboflavin, and Niacin
In India, a human study with 78 patients found that co-administration of tamoxifen with 100 mg CoQ10, 10 mg riboflavin, and 50 mg niacin reverted all lipid and lipoprotein abnormalities back to normal within 90 days of combination therapy (Yuvaraj and Premkumar, 2007). Rats with induced breast cancer treated with tamoxifen and CoQ10, riboflavin, and niacin had near normal levels of lipid peroxide and enzymatic and non-enzymatic antioxidants. Furthermore antitumor activity was enhanced. (Perumal and Shanthi, 2005).

» Coenzyme Q10: Oil softgels have higher absorption. Daily doses of CoQ10 range from 30 mg to 300 mg and is best taken with food. About three weeks of daily dosing are necessary to reach maximal serum concentrations of CoQ10. Bioavailability is increased when combined with piperine. The most advanced version of COQ10 is the more highly absorbable version called Ubiquinol.

» Riboflavin (Vitamin B2): Typical doses can range between 100 mg and 200 mg per day.

» Niacin (Vitamin B3): Typical doses can range between 100 mg and 1200 mg per day. Slow dose escalation is essential to acclimate the body to the “niacin flush”. Some people find that the niacinamide version does not cause flush.

Vitamin C & E
Tamoxifen, a hormonal inhibition treatment for breast cancer, can cause lipid abnormalities. A human study in India found that administering 500 mg vitamin C and 400 mg (or 600 IU) of vitamin E for 90 days to postmenopausal breast cancer patients undergoing tamoxifen treatment significantly decreased the lipid abnormalities (Babu and Sundravel, 2000).

» Vitamin C: The LOAEL (Lowest Observed Adverse Effect Level) is 3,000 mg daily. Many people find that doses above 3,000 mg can cause diarrhea. Using buffered Vitamin C can help reduce stomach and intestinal irritation.

» Vitamin E: Avoid synthetic vitamin E, such as alpha-tocopherol or succinate. Seek out the mixed tocopherols, particularly those containing the vitamin E fractions called tocotrienols and gammatocopherol. Typical dosage ranges from 50 IU to 800 IU daily.

Studies on Combination Chemotherapy Protocols

Cyclophosphamide, Methotrexate, 5-Fluorouracil (CMF)
Melatonin (not as supplement)
A study from Poland discovered that the combination treatment CMF induced an increase in the body’s natural melatonin levels in the blood. These melatonin levels did not differ between women who were tested as healthy controls and women prior to chemotherapy treatment. But following CMF treatment, melatonin was significantly increased. The researchers postulated that this increase may actually be an essential component to successful treatment with CMF (Kajdaniuk and Marek, 2001).

CONCLUSION
This review of research, including laboratory, animal, and human studies, found data in most cases supporting the combination of antioxidants with chemotherapy. Much of the evidence available, however, is from laboratory studies rather than randomized, controlled human studies, so if patients and practitioners decide to use antioxidants, they are faced with some uncertainty as to which antioxidants to use and at which dosages. Further research should help to identify optimal dosing schedules and further investigate the wide range of nutritional and herbal therapies that exist for additional treatment candidates.

When a patient decides not to take antioxidants with chemotherapy, they should discontinue all antioxidants two weeks prior to chemotherapy and not resume until two to three weeks after the last session. The risk is that healthy cells may be less protected against chemotherapy and could include serious consequences such as organ damage and impaired immune function and, therefore, prevent the body’s ability to fight cancer. The cancer itself may also be more able to develop resistance to chemotherapy. The benefit could be that the chemotherapy drugs may work better.

When a patient decides to take antioxidants with chemotherapy, they should continue to take antioxidants before, during, or after chemotherapy in consultation with a knowledgeable practitioner. The risk is that antioxidants could interfere with chemotherapy and cancer cells not killed by the first round may become resistant to future treatment. The benefit is that antioxidants may help chemotherapy work better, protect healthy cells against the harmful effects of chemotherapy, and reduce side effects.

While there is still no consensus among medical practitioners on the issue of whether or not to combine antioxidants with chemotherapy, we hope that this discussion will help patients in the process of informed decision making as they work together with their medical team.

Johanna Altgelt is an associate researcher at the Pine Street Foundation.

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