Ovarian Cancer, Chemotherapy, & Antioxidants

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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REFERENCES

Akcay, T., Y. Dincer, et al. (2005). "Significance of the O6-methylguanine-DNA methyltransferase and glutathione S-transferase activity in the sera of patients with malignant and benign ovarian tumors." Eur J Obstet Gynecol Reprod Biol 119(1): 108-13.

Argyriou, A. A., E. Chroni, et al. (2005). "Vitamin E for prophylaxis against chemotherapy-induced neuropathy: a randomized controlled trial." Neurology 64(1): 26-31.

Bogliun, G., L. Marzorati, et al. (1992). "Evaluation by somatosensory evoked potentials of the neurotoxicity of cisplatin alone or in combination with glutathione." Ital J Neurol Sci 13(8): 643-7.

Bohm, S., G. Battista Spatti, et al. (1991). "A feasibility study of cisplatin administration with low-volume hydration and glutathione protection in the treatment of ovarian carcinoma." Anticancer Res 11(4): 1613-6.

Bohm, S., S. Oriana, et al. (1999). "Dose intensification of platinum compounds with glutathione protection as induction chemotherapy for advanced ovarian carcinoma." Oncology 57(2): 115-20.

Boike, G. M., E. Petru, et al. (1990). "Chemical enhancement of cisplatin cytotoxicity in a human ovarian and cervical cancer cell line." Gynecol Oncol 38(3): 315-22.

Caffrey, P. B. and G. D. Frenkel (2000). "Selenium compounds prevent the induction of drug resistance by cisplatin in human ovarian tumor xenografts in vivo." Cancer Chemother Pharmacol 46(1): 74-8.

Caffrey, P. B., M. Zhu, et al. (1998). "Prevention of the development of melphalan resistance in vitro by selenite." Biol Trace Elem Res 65(3): 187-95.

Chan, M. M., D. Fong, et al. (2003). "Inhibition of growth and sensitization to cisplatin-mediated killing of ovarian cancer cells by polyphenolic chemopreventive agents." J Cell Physiol 194(1): 63-70.

Chen, G., K. J. Hutter, et al. (1995). "Positive correlation between cellular glutathione and acquired cisplatin resistance in human ovarian cancer cells." Cell Biol Toxicol 11(5): 273-81.

Chen, G. and W. J. Zeller (1993). "Reversal of acquired cisplatin resistance by nicotinamide in vitro and in vivo." Cancer Chemother Pharmacol 33(2): 157-62.

Colombo, N., S. Bini, et al. (1995). "Weekly cisplatin +/- glutathione in relapsed ovarian carcinoma." Int J Gynecol Cancer 5(2): 81-86.

Das, G. C., A. Bacsi, et al. (2006). "Enhanced gamma-glutamylcysteine synthetase activity decreases drug-induced oxidative stress levels and cytotoxicity." Mol Carcinog 45(9): 635-47.

Di Re, F., S. Bohm, et al. (1993). "High-dose cisplatin and cyclophosphamide with glutathione in the treatment of advanced ovarian cancer." Ann Oncol 4(1): 55-61.

Di Re, F., S. Bohm, et al. (1990). "Efficacy and safety of high-dose cisplatin and cyclophosphamide with glutathione protection in the treatment of bulky advanced epithelial ovarian cancer." Cancer Chemother Pharmacol 25(5): 355-60.

Drisko, J. A., J. Chapman, et al. (2003). "The use of antioxidants with first-line chemotherapy in two cases of ovarian cancer." J Am Coll Nutr 22(2): 118-23.

Dufour, M., L. C. Panasci, et al. (1985). "Effects of amino acids on the transport and cytotoxicity of melphalan by human bone marrow cells and human tumor cells." Cancer Chemother Pharmacol 15(2): 125-31.

Ferry, D. R., A. Smith, et al. (1996). "Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition." Clin Cancer Res 2(4): 659-68.

Frenkel, G. D. and P. B. Caffrey (2001). "A prevention strategy for circumventing drug resistance in cancer chemotherapy." Curr Pharm Des 7(16): 1595-614.

Futagami, M., S. Sato, et al. (2001). "Effects of melatonin on the proliferation and cis-diamminedichloroplatinum (CDDP) sensitivity of cultured human ovarian cancer cells." Gynecol Oncol 82(3): 544-9.

Gercel-Taylor, C., A. K. Feitelson, et al. (2004). "Inhibitory effect of genistein and daidzein on ovarian cancer cell growth." Anticancer Res 24(2B): 795-800.

Giacomelli, S., D. Gallo, et al. (2002). "Silybin and its bioavailable phospholipid complex (IdB 1016) potentiate in vitro and in vivo the activity of cisplatin." Life Sci 70(12): 1447-59.

Goto, T., M. Takano, et al. (2008). "The involvement of FOXO1 in cytotoxic stress and drug-resistance induced by paclitaxel in ovarian cancers." Br J Cancer 98(6): 1068-75.

Khan, M., J. C. Shobha, et al. (2005). "Protective effect of Spirulina against doxorubicin-induced cardiotoxicity." Phytother Res 19(12): 1030-7.

Kikuchi, Y., H. Sasa, et al. (1991). "Inhibition of human ovarian cancer cell proliferation in vitro by ginsenoside Rh2 and adjuvant effects to cisplatin in vivo." Anticancer Drugs 2(1): 63-7.

Kobayashi, Y., K. Kariya, et al. (1994). "Enhancement of anti-cancer activity of cisdiaminedichloroplatinum by the protein-bound polysaccharide of Coriolus versicolor QUEL (PS-K) in vitro." Cancer Biother 9(4): 351-8.

Krychman, M. L., J. Carter, et al. (2004). "Chemotherapy-induced dyspareunia: a case study of vaginal mucositis and pegylated liposomal doxorubicin injection in advanced stage ovarian carcinoma." Gynecol Oncol 93(2): 561-3.

Kudoh, K., T. Kita, et al. (1994). "[Potentiation of cisplatin sensitivity of cisplatin-resistant human ovarian cancer cell lines by L-buthionine-S,R-sulfoximine]." Nippon Sanka Fujinka Gakkai Zasshi 46(6): 525-32.

Lewandowicz, G. M., P. Britt, et al. (2002). "Cellular glutathione content, in vitro chemoresponse, and the effect of BSO modulation in samples derived from patients with advanced ovarian cancer." Gynecol Oncol 85(2): 298-304.

Locatelli, M. C., A. D'Antona, et al. (1993). "A phase II study of combination chemotherapy in advanced ovarian carcinoma with cisplatin and cyclophosphamide plus reduced glutathione as potential protective agent against cisplatin toxicity." Tumori 79(1): 37-9.

Lopez, A. M., L. Wallace, et al. (1999). "Topical DMSO treatment for pegylated liposomal doxorubicin-induced palmar-plantar erythrodysesthesia." Cancer Chemother Pharmacol 44(4): 303-6.

Maier, R. H., S. M. Purser, et al. (1997). "The cytotoxic interaction of inorganic trace elements with EDTA and cisplatin in sensitive and resistant human ovarian cancer cells." In Vitro Cell Dev Biol Anim 33(3): 218-21.

Manusirivithaya, S., M. Sripramote, et al. (2004). "Antiemetic effect of ginger in gynecologic oncology patients receiving cisplatin." Int J Gynecol Cancer 14(6): 1063-9.

Melichar, B., H. Kalabova, et al. (2007). "Serum alpha-tocopherol, retinol and neopterin during paclitaxel/carboplatin chemotherapy." Anticancer Res 27(6C): 4397-401.

Nakata, H., Y. Kikuchi, et al. (1998). "Inhibitory effects of ginsenoside Rh2 on tumor growth in nude mice bearing human ovarian cancer cells." Jpn J Cancer Res 89(7): 733-40.

Ness, R. B. and C. Cottreau (1999). "Possible role of ovarian epithelial inflammation in ovarian cancer." J Natl Cancer Inst 91(17): 1459-67.

Oriana, S., S. Bohm, et al. (1987). "A preliminary clinical experience with reduced glutathione as protector against cisplatin-toxicity." Tumori 73(4): 337-40.

Pace, A., A. Savarese, et al. (2003). "Neuroprotective effect of vitamin E supplementation in patients treated with cisplatin chemotherapy." J Clin Oncol 21(5): 927-31.

Parekh, H. and H. Simpkins (1996). "Cross-resistance and collateral sensitivity to natural product drugs in cisplatin-sensitive and -resistant rat lymphoma and human ovarian carcinoma cells." Cancer Chemother Pharmacol 37(5): 457-62.

Pirovano, C., A. Balzarini, et al. (1992). "Peripheral neurotoxicity following high-dose cisplatin with glutathione: clinical and neurophysiological assessment." Tumori 78(4): 253-7.

Pisano, C., G. Pratesi, et al. (2003). "Paclitaxel and Cisplatin-induced neurotoxicity: a protective role of acetyl-L-carnitine." Clin Cancer Res 9(15): 5756-67.

Scambia, G., R. De Vincenzo, et al. (1996). "Antiproliferative effect of silybin on gynaecological malignancies: synergism with cisplatin and doxorubicin." Eur J Cancer 32A(5): 877-82.

Scambia, G., F. O. Ranelletti, et al. (1990). "Synergistic antiproliferative activity of quercetin and cisplatin on ovarian cancer cell growth." Anticancer Drugs 1(1): 45-8.

Schiano, M. A., B. U. Sevin, et al. (1991). "In vitro enhancement of cis-platinum antitumor activity by caffeine and pentoxifylline in a human ovarian cell line." Gynecol Oncol 43(1): 37-45.

Senthil, K., S. Aranganathan, et al. (2004). "Evidence of oxidative stress in the circulation of ovarian cancer patients." Clin Chim Acta 339(1-2): 27-32.

Sharp, S. Y., V. Smith, et al. (1998). "Lack of a role for MRP1 in platinum drug resistance in human ovarian cancer cell lines." Br J Cancer 78(2): 175-80.

Shen, F. and G. Weber (1997). "Synergistic action of quercetin and genistein in human ovarian carcinoma cells." Oncol Res 9(11-12): 597-602.

Shimizu, Y., K. Hasumi, et al. (1989). "[Successful treatment of a patient with recurrent ovarian cancer by lentinan combined with intraarterial 5FU]." Nippon Gan Chiryo Gakkai Shi 24(3): 647-51.

Sieja, K. and M. Talerczyk (2004). "Selenium as an element in the treatment of ovarian cancer in women receiving chemotherapy." Gynecol Oncol 93(2): 320-7.

Smyth, J. F., A. Bowman, et al. (1997). "Glutathione reduces the toxicity and improves quality of life of women diagnosed with ovarian cancer treated with cisplatin: results of a double-blind, randomised trial." Ann Oncol 8(6): 569-73.

Sugiyama, T. and Y. Sadzuka (1998). "Enhancing effects of green tea components on the antitumor activity of adriamycin against M5076 ovarian sarcoma." Cancer Lett 133(1): 19-26.

Sugiyama, T. and Y. Sadzuka (1999). "Combination of theanine with doxorubicin inhibits hepatic metastasis of M5076 ovarian sarcoma." Clin Cancer Res 5(2): 413-6.

Sundstrom, H., E. Yrjanheikki, et al. (1984). "Serum selenium in patients with ovarian cancer during and after therapy." Carcinogenesis 5(6): 731-4.

Tode, T., Y. Kikuchi, et al. (1992). "[In vitro and in vivo effects of ginsenoside Rh2 on the proliferation of serous cystadenocarcinoma of the human ovary]." Nippon Sanka Fujinka Gakkai Zasshi 44(5): 589-94.

van Acker, S. A., E. Boven, et al. (1997). "Monohydroxyethylrutoside, a dose-dependent cardioprotective agent, does not affect the antitumor activity of doxorubicin." Clin Cancer Res 3(10): 1747-54.

Vistica, D. T., D. D. Von Hoff, et al. (1981). "Uptake of melphalan by human ovarian carcinoma cells and its relationship to the amino acid content of ascitic fluid." Cancer Treat Rep 65(1-2): 157-61.

Xu, T. M., Y. Xin, et al. (2007). "Inhibitory effect of ginsenoside Rg3 combined with cyclophosphamide on growth and angiogenesis of ovarian cancer." Chin Med J (Engl) 120(7): 584-8.

Zeller, W. J., S. Fruhauf, et al. (1991). "Chemoresistance in rat ovarian tumours." Eur J Cancer 27(1): 62-7.

INTRODUCTIONOxidative 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

LENTINANLentinan 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-CARNITINEAcetyl-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)CAFFEINECaffeine 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)CURCUMINCurcumin 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)EGCGEpigallocatechin-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)GENISTEINGenistein 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 GINSENGGinsenosides 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 levelsof 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)GINGERGinger, 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)GLUTATHIONEGlutathione 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)MELATONINMelatonin 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)QUERCETINQuercetin 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)RESVERATROLResveratrol 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 HESPERIDINThe 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)SELENIUMSelenium 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)SILYBINSilybin (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 B3Niacin (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 EVitamin 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

GLUTATHIONEResearchers 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 EPeripheral 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 3In 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 NIACINIn 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)GLUTATHIONEIn 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)SPIRULINASpirulina 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)THEANINETheanine 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 EIn 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

CURCUMINIn 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

GENISTEINIn 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

SELENITEIn 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 TYROSINEIn 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-ACETYLCYSTEINEIn 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 Q10Vitamin 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 AVitamin 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

QUECETINIn 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)Top of Page....................................................................................................................REFERENCES Akcay, T., Y. Dincer, et al. (2005). "Significance of the O6-methylguanine-DNA methyltransferase and glutathione S-transferase activity in the sera of patients with malignant and benign ovarian tumors." Eur J Obstet Gynecol Reprod Biol 119(1): 108-13.Argyriou, A. A., E. Chroni, et al. (2005). "Vitamin E for prophylaxis against chemotherapy-induced neuropathy: a randomized controlled trial." Neurology 64(1): 26-31.Bogliun, G., L. Marzorati, et al. (1992). "Evaluation by somatosensory evoked potentials of the neurotoxicity of cisplatin alone or in combination with glutathione." Ital J Neurol Sci 13(8): 643-7.Bohm, S., G. Battista Spatti, et al. (1991). "A feasibility study of cisplatin administration with low-volume hydration and glutathione protection in the treatment of ovarian carcinoma." Anticancer Res 11(4): 1613-6.Bohm, S., S. Oriana, et al. (1999). "Dose intensification of platinum compounds with glutathione protection as induction chemotherapy for advanced ovarian carcinoma." Oncology 57(2): 115-20.Boike, G. M., E. Petru, et al. (1990). "Chemical enhancement of cisplatin cytotoxicity in a human ovarian and cervical cancer cell line." Gynecol Oncol 38(3): 315-22.Caffrey, P. B. and G. D. Frenkel (2000). "Selenium compounds prevent the induction of drug resistance by cisplatin in human ovarian tumor xenografts in vivo." Cancer Chemother Pharmacol 46(1): 74-8.Caffrey, P. B., M. Zhu, et al. (1998). "Prevention of the development of melphalan resistance in vitro by selenite." Biol Trace Elem Res 65(3): 187-95.Chan, M. M., D. Fong, et al. (2003). "Inhibition of growth and sensitization to cisplatin-mediated killing of ovarian cancer cells by polyphenolic chemopreventive agents." J Cell Physiol 194(1): 63-70.Chen, G., K. J. Hutter, et al. (1995). "Positive correlation between cellular glutathione and acquired cisplatin resistance in human ovarian cancer cells." Cell Biol Toxicol 11(5): 273-81.Chen, G. and W. J. Zeller (1993). "Reversal of acquired cisplatin resistance by nicotinamide in vitro and in vivo." Cancer Chemother Pharmacol 33(2): 157-62.Colombo, N., S. Bini, et al. (1995). "Weekly cisplatin +/- glutathione in relapsed ovarian carcinoma." Int J Gynecol Cancer 5(2): 81-86.Das, G. C., A. Bacsi, et al. (2006). "Enhanced gamma-glutamylcysteine synthetase activity decreases drug-induced oxidative stress levels and cytotoxicity." Mol Carcinog 45(9): 635-47.Di Re, F., S. Bohm, et al. (1993). "High-dose cisplatin and cyclophosphamide with glutathione in the treatment of advanced ovarian cancer." Ann Oncol 4(1): 55-61.Di Re, F., S. Bohm, et al. (1990). "Efficacy and safety of high-dose cisplatin and cyclophosphamide with glutathione protection in the treatment of bulky advanced epithelial ovarian cancer." Cancer Chemother Pharmacol 25(5): 355-60.Drisko, J. A., J. Chapman, et al. (2003). "The use of antioxidants with first-line chemotherapy in two cases of ovarian cancer." J Am Coll Nutr 22(2): 118-23.Dufour, M., L. C. Panasci, et al. (1985). "Effects of amino acids on the transport and cytotoxicity of melphalan by human bone marrow cells and human tumor cells." Cancer Chemother Pharmacol 15(2): 125-31.Ferry, D. R., A. Smith, et al. (1996). "Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition." Clin Cancer Res 2(4): 659-68.Frenkel, G. D. and P. B. Caffrey (2001). "A prevention strategy for circumventing drug resistance in cancer chemotherapy." Curr Pharm Des 7(16): 1595-614.Futagami, M., S. Sato, et al. (2001). "Effects of melatonin on the proliferation and cis-diamminedichloroplatinum (CDDP) sensitivity of cultured human ovarian cancer cells." Gynecol Oncol 82(3): 544-9.Gercel-Taylor, C., A. K. Feitelson, et al. (2004). "Inhibitory effect of genistein and daidzein on ovarian cancer cell growth." Anticancer Res 24(2B): 795-800.Giacomelli, S., D. Gallo, et al. (2002). "Silybin and its bioavailable phospholipid complex (IdB 1016) potentiate in vitro and in vivo the activity of cisplatin." Life Sci 70(12): 1447-59.Goto, T., M. Takano, et al. (2008). "The involvement of FOXO1 in cytotoxic stress and drug-resistance induced by paclitaxel in ovarian cancers." Br J Cancer 98(6): 1068-75.Khan, M., J. C. Shobha, et al. (2005). "Protective effect of Spirulina against doxorubicin-induced cardiotoxicity." Phytother Res 19(12): 1030-7.Kikuchi, Y., H. Sasa, et al. (1991). "Inhibition of human ovarian cancer cell proliferation in vitro by ginsenoside Rh2 and adjuvant effects to cisplatin in vivo." Anticancer Drugs 2(1): 63-7.Kobayashi, Y., K. Kariya, et al. (1994). "Enhancement of anti-cancer activity of cisdiaminedichloroplatinum by the protein-bound polysaccharide of Coriolus versicolor QUEL (PS-K) in vitro." Cancer Biother 9(4): 351-8.Krychman, M. L., J. Carter, et al. (2004). "Chemotherapy-induced dyspareunia: a case study of vaginal mucositis and pegylated liposomal doxorubicin injection in advanced stage ovarian carcinoma." Gynecol Oncol 93(2): 561-3.Kudoh, K., T. Kita, et al. (1994). "[Potentiation of cisplatin sensitivity of cisplatin-resistant human ovarian cancer cell lines by L-buthionine-S,R-sulfoximine]." Nippon Sanka Fujinka Gakkai Zasshi 46(6): 525-32.Lewandowicz, G. M., P. Britt, et al. (2002). "Cellular glutathione content, in vitro chemoresponse, and the effect of BSO modulation in samples derived from patients with advanced ovarian cancer." Gynecol Oncol 85(2): 298-304.Locatelli, M. C., A. D'Antona, et al. (1993). "A phase II study of combination chemotherapy in advanced ovarian carcinoma with cisplatin and cyclophosphamide plus reduced glutathione as potential protective agent against cisplatin toxicity." Tumori 79(1): 37-9.Lopez, A. M., L. Wallace, et al. (1999). "Topical DMSO treatment for pegylated liposomal doxorubicin-induced palmar-plantar erythrodysesthesia." Cancer Chemother Pharmacol 44(4): 303-6.Maier, R. H., S. M. Purser, et al. (1997). "The cytotoxic interaction of inorganic trace elements with EDTA and cisplatin in sensitive and resistant human ovarian cancer cells." In Vitro Cell Dev Biol Anim 33(3): 218-21.Manusirivithaya, S., M. Sripramote, et al. (2004). "Antiemetic effect of ginger in gynecologic oncology patients receiving cisplatin." Int J Gynecol Cancer 14(6): 1063-9.Melichar, B., H. Kalabova, et al. (2007). "Serum alpha-tocopherol, retinol and neopterin during paclitaxel/carboplatin chemotherapy." Anticancer Res 27(6C): 4397-401.Nakata, H., Y. Kikuchi, et al. (1998). "Inhibitory effects of ginsenoside Rh2 on tumor growth in nude mice bearing human ovarian cancer cells." Jpn J Cancer Res 89(7): 733-40.Ness, R. B. and C. Cottreau (1999). "Possible role of ovarian epithelial inflammation in ovarian cancer." J Natl Cancer Inst 91(17): 1459-67.Oriana, S., S. Bohm, et al. (1987). "A preliminary clinical experience with reduced glutathione as protector against cisplatin-toxicity." Tumori 73(4): 337-40.Pace, A., A. Savarese, et al. (2003). "Neuroprotective effect of vitamin E supplementation in patients treated with cisplatin chemotherapy." J Clin Oncol 21(5): 927-31.Parekh, H. and H. Simpkins (1996). "Cross-resistance and collateral sensitivity to natural product drugs in cisplatin-sensitive and -resistant rat lymphoma and human ovarian carcinoma cells." Cancer Chemother Pharmacol 37(5): 457-62.Pirovano, C., A. Balzarini, et al. (1992). "Peripheral neurotoxicity following high-dose cisplatin with glutathione: clinical and neurophysiological assessment." Tumori 78(4): 253-7.Pisano, C., G. Pratesi, et al. (2003). "Paclitaxel and Cisplatin-induced neurotoxicity: a protective role of acetyl-L-carnitine." Clin Cancer Res 9(15): 5756-67.Scambia, G., R. De Vincenzo, et al. (1996). "Antiproliferative effect of silybin on gynaecological malignancies: synergism with cisplatin and doxorubicin." Eur J Cancer 32A(5): 877-82.Scambia, G., F. O. Ranelletti, et al. (1990). "Synergistic antiproliferative activity of quercetin and cisplatin on ovarian cancer cell growth." Anticancer Drugs 1(1): 45-8.Schiano, M. A., B. U. Sevin, et al. (1991). "In vitro enhancement of cis-platinum antitumor activity by caffeine and pentoxifylline in a human ovarian cell line." Gynecol Oncol 43(1): 37-45.Senthil, K., S. Aranganathan, et al. (2004). "Evidence of oxidative stress in the circulation of ovarian cancer patients." Clin Chim Acta 339(1-2): 27-32.Sharp, S. Y., V. Smith, et al. (1998). "Lack of a role for MRP1 in platinum drug resistance in human ovarian cancer cell lines." Br J Cancer 78(2): 175-80.Shen, F. and G. Weber (1997). "Synergistic action of quercetin and genistein in human ovarian carcinoma cells." Oncol Res 9(11-12): 597-602.Shimizu, Y., K. Hasumi, et al. (1989). "[Successful treatment of a patient with recurrent ovarian cancer by lentinan combined with intraarterial 5FU]." Nippon Gan Chiryo Gakkai Shi 24(3): 647-51.Sieja, K. and M. Talerczyk (2004). "Selenium as an element in the treatment of ovarian cancer in women receiving chemotherapy." Gynecol Oncol 93(2): 320-7.Smyth, J. F., A. Bowman, et al. (1997). "Glutathione reduces the toxicity and improves quality of life of women diagnosed with ovarian cancer treated with cisplatin: results of a double-blind, randomised trial." Ann Oncol 8(6): 569-73.Sugiyama, T. and Y. Sadzuka (1998). "Enhancing effects of green tea components on the antitumor activity of adriamycin against M5076 ovarian sarcoma." Cancer Lett 133(1): 19-26.Sugiyama, T. and Y. Sadzuka (1999). "Combination of theanine with doxorubicin inhibits hepatic metastasis of M5076 ovarian sarcoma." Clin Cancer Res 5(2): 413-6.Sundstrom, H., E. Yrjanheikki, et al. (1984). "Serum selenium in patients with ovarian cancer during and after therapy." Carcinogenesis 5(6): 731-4.Tode, T., Y. Kikuchi, et al. (1992). "[In vitro and in vivo effects of ginsenoside Rh2 on the proliferation of serous cystadenocarcinoma of the human ovary]." Nippon Sanka Fujinka Gakkai Zasshi 44(5): 589-94.van Acker, S. A., E. Boven, et al. (1997). "Monohydroxyethylrutoside, a dose-dependent cardioprotective agent, does not affect the antitumor activity of doxorubicin." Clin Cancer Res 3(10): 1747-54.Vistica, D. T., D. D. Von Hoff, et al. (1981). "Uptake of melphalan by human ovarian carcinoma cells and its relationship to the amino acid content of ascitic fluid." Cancer Treat Rep 65(1-2): 157-61.Xu, T. M., Y. Xin, et al. (2007). "Inhibitory effect of ginsenoside Rg3 combined with cyclophosphamide on growth and angiogenesis of ovarian cancer." Chin Med J (Engl) 120(7): 584-8.Zeller, W. J., S. Fruhauf, et al. (1991). "Chemoresistance in rat ovarian tumours." Eur J Cancer 27(1): 62-7.