Breast Cancer, Chemotherapy, & Antioxidants

INTRODUCTION
Chemotherapy is standard care for many women with breast cancer. While this treatment is often beneficial, there are some notable drawbacks, including the fact that breast cancer cells can become resistant to chemotherapy and that side effects can be debilitating and intolerable.

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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