Prevention of Chemotherapy and Radiation Therapy Toxicities by Micronutrients

Many cancer patients have micronutrient deficiencies that may be further aggravated by radiation therapy or chemotherapy. Significant morbidity and mortality may result from treatment-induced deficiencies of micronutrients because of the important roles these compounds play in critical cellular functions. Adverse effects of chemotherapy and radiation therapy may also be enhanced in the presence of micronutrient deficiency. Possible benefits of micronutrient supplementation in cancer patients undergoing chemotherapy and/or radiation therapy include decreased adverse effects of treatment, improved immune function, increased tumor response to treatment, and improved quality of life. Future clinical studies should investigate the potential benefits and risks of various micronutrients as an adjunct to chemotherapy and radiation therapy.

Micronutrients Antioxidants Chemotherapy Radiation

Toxicity prevention

Micronutrients and Cancer

Epidemiological data consistently show an inverse relationship between cancer risk and dietary intake of vegetables and fruits or their antioxidant micronutrients ( 8). Most cancer patients have low micronutrient levels at presentation. Cancer is a disease of aging, and micronutrient deficiencies are more common among older individuals. Monget et al. ( 67) found that serum concentrations of most micronutrients had a negative correlation with age and most elderly nursing home residents had low serum levels of vitamin C, zinc, and selenium. Micronutrient deficiency may also be present in nongeriatric cancer patients. Donma et al. ( 20) found reduced hair zinc levels in children with malignancies compared to healthy children and children with cancers in complete remission. Melichar et al. ( 61) found increased urinary excretion of zinc in cancer patients and this significantly correlated with poor renal tubular function.

Tobacco consumption is a major risk factor for many human cancers. Tobacco use has consistently been associated with increased oxidative stress and decreased serum antioxidant micronutrient levels. Pamuk et al. ( 74) reported on the relationship between current cigarette smoking and serum concentrations of vitamins C, E, and A, and five carotenoids in 91 low-income, African-American women. Among smokers, serum concentrations of alpha-carotene, beta-carotene, cryptoxanthin, and lycopene averaged only 71-79% of the concentrations among nonsmokers. Mean serum concentrations of vitamins C and E and lutein/zeaxanthin were only slightly lower among smokers relative to nonsmokers. Among current smokers, mean serum concentrations of all five carotenoids decreased with an increase in the amount smoked. Ross et al. ( 82) determined plasma concentrations of carotenoids, ascorbic acid, alpha-tocopherol, and gamma-tocopherol in plasmas from 50 smokers and 50 age-matched never-smoker Scottish men. Significantly less alpha-carotene, beta-carotene, cyrptoxanthin, and ascorbic acid were found in smokers compared to persons who never smoked. Pakrashi and Chatterjee ( 73) measured prostatic excretion of zinc in ejaculates of 29 tobacco smokers, 25 tobacco chewers, and 30 nonusers of tobacco. They found reduced levels of zinc in the ejaculates of tobacco smokers compared to tobacco chewers and tobacco nonusers. Faruque et al. ( 25) observed lower dietary intake of vitamin C, carotenoids, and zinc and lower plasma level of vitamin C in 44 male students who smoked compared to 44 male nonsmoker students.

Alcohol consumption has also been associated with increased oxidative stress and decreased micronutrient levels. Alcohol and tobacco in combination may result in even more severe micronutrient deficiencies compared to either one used alone. Tsubono et al. ( 108) examined the associations of smoking and alcohol with plasma levels of beta-carotene, alpha-carotene, lutein, lycopene, and zeaxanthin in 634 healthy men aged 40-49 years. After controlling for age, serum cholesterol, serum triglycerides, body mass index, green vegetables, yellow vegetables, and fruits, there was a significant inverse association between smoking and alcohol consumption and plasma levels of beta-carotene and alpha-carotene; only smoking reduced the level of lutein, and neither smoking nor alcohol significantly reduced the level of lycopene or zeaxanthin. Brady et al. ( 13), in a population-based sample of 400 individuals, found an association between smoking and alcohol consumption and lower serum levels of alpha-carotene, beta-carotene, beta-cryptoxanthin, and lutein/zeaxanthin. In addition, lower serum lycopene was associated with older age. Lecomte et al. ( 54) measured plasma carotenoid levels in 118 healthy men consuming low or moderate alcohol and 95 alcoholics. Beta-carotene, alpha-carotene, zeaxanthin-lutein, lycopene, and beta-cryptoxanthin levels were significantly lower in alcoholics, and 21 days after withdrawal plasma levels of all carotenoids increased. However, Leo et al. ( 55) did not find a significant difference in the levels of carotenoids, retinol, and alpha-tocopherol from oropharyngeal mucosa samples of 11 chronic alcoholics with oropharyngeal cancer and 11 control subjects.

Nutritional status is known to profoundly impact treatment morbidity, efficacy, and overall prognosis in cancer patients ( 6, 14, 15, 40, 46, 68, 96, 114). Various prognostic nutritional indices have been developed to predict treatment complications and overall survival ( 14, 15, 40, 46). Radiation and chemotherapy are better tolerated and may be more effective in nutritionally sound individuals ( 14, 40). For example, head and neck cancer patients with poor nutritional status are at increased risk for postoperative wound breakdown and infections, fistula formation, and flap loss ( 40, 46). These patients frequently present with significant weight loss and chronic protein-calorie malnutrition, which may be exacerbated by an acute weight loss due to decreased intake secondary to tumor-induced dysphagia ( 6, 14, 40, 46, 114). Approximately 30-40% of patients with advanced stage head and neck cancer have severe malnutrition and an additional 20-30% have moderate malnutrition at the time of presentation ( 6, 14, 40, 46, 114). Olmedilla et al. ( 71) found that the plasma levels of carotenoids, retinol, and vitamin E were significantly lower in patients who had laryngectomy for laryngeal cancer compared to control subjects. After commercial enteral formula feeding carotenoid levels further decreased and retinol and tocopherol levels increased; however, the levels remained lower than the controls for all micronutrients ( 71). Postoperative alterations of the upper aerodigestive tract may further compromise intake, increase metabolic demands, and compound the nutritional stress ( 96, 114). Because there are no known zinc stores in the human body, zinc deficiency sets in quickly with malnutrition in these patients ( 77).

Zinc deficiency causes a profound reduction in the activity of a thymic hormone, thymulin. Prasad et al. ( 78) found decreased production of interleukin-2 and interferon-gamma by TH 1 cells, reduced NK cell activity, and decreased recruitment of T-cell precursors in zinc-deficient subjects. Mocchegiani observed a significant increase or stabilization in body weight of AIDS patients who received zinc supplement in addition to AZT, associated with an increase in CD4 cells and plasma thymulin and decrease in the frequency of opportunistic infections ( 65). Abdulla et al. ( 2) observed that plasma zinc was decreased and the copper/zinc ratio in the plasma was significantly higher in 13 patients with squamous cell carcinoma of the head and neck in comparison to the healthy controls. Those patients who showed a marked decrease in plasma zinc levels died within 12 months. The authors suggested that plasma zinc and copper/zinc ratio may be of value as a potential screening and predicting test in patients with head and neck cancer. However, Garofalo et al. ( 31) observed no significant difference in serum zinc and observed no diagnostic or prognostic value in these parameters in patients with head and neck cancer.

Nutritional Consequences of Radiation and Chemotherapy

Both radiation therapy and chemotherapy have been associated with increased oxidative stress, which may further deplete tissue levels of antioxidant micronutrients, particularly in smokers and in the presence of inadequate dietary intake. Faber et al. ( 23) measured lipid peroxidation, plasma glutathione and glutathione peroxidase activity, and plasma micronutrient levels in patients with cancer before and after doxorubicin-containing chemotherapy. The concentration lipid peroxidation products, measured as thiobarbituric acid reactant materials, in the plasma of cancer patients was higher than in controls and the level was further increased after chemotherapy. These results indicated that cancer patients had increased oxidative stress at presentation that was further aggravated by doxorubicin treatment. Cancer patients had lower levels of glutathione, glutathione peroxidase, selenium, and zinc, but these were not further modified by chemotherapy. Torii et al. ( 107) reported that doxorubicin treatment caused cardiomyopathy and increased lipid peroxidation and lower alpha-tocopherol levels in the myocardium of spontaneously hypertensive rats.

Radiation therapy of malignancies in the head and neck area results in a marked reduction in saliva flow rate and alterations in saliva composition within the first week of therapy and impairs saliva flow throughout the duration of therapy. Decreased secretion of saliva may lead to symptoms such as oral pain and and burning sensations, loss of taste and appetite, and increased incidence of oral disease. These symptoms may affect eating and increase the risk of inadequate nutritional intake. Backstrom et al. ( 3) investigated the average nutritional intake of 24 patients treated for malignancies in the head and neck region who had dry mouth symptoms that had persisted for at least 4 months after the completion of radiation therapy. The average caloric intake was 1925 calories in the irradiated patients with dry mouth symptoms compared to 2219 calories in the age- and sex-matched controls. The average intakes of vitamin A, beta-carotene, vitamin E, vitamin B( 6), folic acid, iron, and zinc were significantly lower in the irradiated patients than in controls.

Effects of Selected Micronutrients on Radiation and Chemotherapy Toxicity (Table 1)

Vitamin E

Many toxicities associated with chemotherapy and/or radiation therapy may be preventable by vitamin E administration. Radioprotection by vitamin E may in part be due to its antioxidant effects ( 58) and in part due to its immunostimulatory and immunoprotective effects ( 86, 87, 99, 106). Vitamin E was found to be effective in preventing chemotherapy-induced oral mucositis ( 56, 110), and protected against doxorubicin cardiotoxicity without compromising the effectiveness of the drug ( 69). The efficacy of vitamin E in selective protection of murine erythroid progenitor cells from chemotherapy toxicity ( 39) as well as prevention of severe toxicity caused by tumor necrosis factor ( 94) have been reported. Selective antitumor effect of alpha-tocopherol against murine leukemia cells while protecting the murine bone marrow against doxorubicin toxicity has also been reported ( 24). Srinivasan and Weiss ( 100) showed that pretreatment with alpha-tocopherol protected mice against radiation lethality and the effect of another radioprotective agent, WR-3689, was enhanced when given in combination with vitamin E. Nattakom et al. ( 70) reported the case of a 44-year-old woman who developed severe veno-occlusive disease after bone marrow transplantation and was treated with vitamin E and glutamine, which resulted in complete resolution of the clinical and biochemical signs of severe hepatic dysfunction associated with this disease.

In addition to its cardioprotective effect, alpha-tocopherol pretreatment prevented the development of doxorubicin-induced focal glomerulosclerosis and renal failure in an animal model ( 112). Topical application of vitamin E was also very effective in promoting the healing of skin wounds caused by doxorubicin-induced skin necrosis ( 57). In animals given an oral or topical vitamin E preparation prior to treatment with doxorubicin, dermal incision wounds healed much better compared to control animals, suggesting that vitamin E may play an important role in postoperative wound healing, especially in doxorubicin-impaired wounds ( 7).

Oral administration of vitamin E concurrently with intravenous chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in rats protected the intestinal membranes against chemotherapy-induced toxicity ( 103). CMF induced decreases in intestinal basolateral membrane levels of ATPases, alkaline phosphatase, 5' -nucleotidase and sulfhydryl groups, and increase in malondialdehyde levels were restored to normal by coadministration of vitamin E. Vascular endothelial damage induced by intravenous cisplatin administration was prevented by vitamin E treatment in rats ( 47). In the cisplatin plus vitamin E group there was restoration of cisplatin-induced morphological changes in the endothelium as well as restoration of superoxide dismutase and Na/K-ATPase levels.

Zinc

Sorenson, in a review article ( 98), has listed copper, iron, manganese, and zinc complexes as protective agents against radiation-induced immunosuppression, cell damage, and death in lethally irradiated animals. Srivastava et al. ( 101) have observed decreased platinum-induced nephrotoxicity and gastrointestinal toxicity in animals given zinc-chelate of histidine before chemotherapy treatment.

Radiation therapy to the head and neck region frequently results in xerostomia and lack of taste. Abnormalities of taste have been realated to a deficiency of zinc in humans by several investigators ( 44, 59). Decreased taste acuity (hypogeusia) has been observed in zinc-deficient subjects, such as patients with liver disease, malabsorption syndrome, chronic uremia, and after bums and administration of penicillamine. Chronically debilitated patients, such as cancer patients, also develop hypogeusia. Mahajan et al. ( 59) showed in a double blind study that zinc was effective in improving taste acuity in subjects with chronic uremia.

Another neurosensory disorder, abnormal dark adaptation, has been also related to a deficiency of zinc in human subjects ( 111). Zinc supplementation to zinc-deficient sickle cell anemia patients is known to correct this abnormality ( 111). Decreased dark adaptation has recently been identified as the dose-limiting toxicity for fenretinide ( 4-hydroxyphenylretinamide), a cancer chemopreventive retinoid compound currently under intensive clinical investigation. Clinical trials should be conducted with combination of zinc and fenretinide to determine if the combination will have decreased fenretinide toxicity and possibly enhanced chemopreventive activity.

Prevention of Selected Chemotherapy and Radiotherapy Toxicities by Micronutrients

Oral and Gastrointestinal Toxicity

Antioxidant micronutrients have been found to prevent gastrointestinal toxicities of radiation and chemotherapy. Mills reported that beta-carotene decreases the oral mucositis that is induced by chemotherapy and radiation therapy ( 63). Klimberg et al. ( 50) observed a protective effect of glutamine on the small bowel mucosa of rats receiving abdominal radiation. Carroll et al. ( 16) found that pretreatment with a variety of antioxidant compounds and micronutrients, including ribose-cystein, amifostine, glutamine, vitamin E, magnesium chloride/ATP, afforded protection against radiation-induced small bowel and large bowel injury in rats.

Cardiotoxicity

Various micronutrients and other micronutrient compounds have been used in the prevention of doxorubicin-induced cardiotoxicity. In an animal model benzylideneascorbate protected against doxorubicin-induced cardiotoxicity whereas ascorbate, 6-palmitoylascorbate, and cysteamine were ineffective ( 52). In vitro studies showed that benzylideneascorbate was a very effective antioxidant, scavenging both superoxide anion and hydroxyl radical and preventing auto-oxidation of linoleic acid ( 52). Glutathione at biological concentrations decreased doxorubicin-dependent rat hepatic microsomal lipid peroxidation, whereas acetylcystein had no effect ( 76). This inhibition appears to be enzyme dependent and requires tocopherol, and a similar mechanism appears to be present in heart microsomal membranes ( 76). Geetha has reported the effects of doxorubicin on rat heart mitochondria ( 32, 33) and lysozymes ( 34). Doxorubicin caused swelling, lipid peroxidation, and thiol depletion in vitro in rat mitochondria and this effect was preventable by adding alpha-tocopherol pretreatment of the animals ( 32). In vivo chronic doxorubicin treatment caused decreased activities of NADH/dehydrogenase, cytochrome C/oxidase and Na/K-ATPase in rat heart mitochondria and this effect was preventable by concurrent oral administration of alpha-tocopherol ( 33). In vivo effects of chronic doxorubicin treatment on rat heart lysosomes showed decrease in the activities of acid phosphatase, beta-D-glucuronidase, cathepsin D, and beta-D-galactosidase with a concomitant increase in microsomal lipid peroxide; these effects were preventable by oral administration of tocopherol concurrently with doxorubicin ( 34). Hida et al. ( 45) showed that in vitro stimulation of microsomal lipid peroxidation is preventable by zinc, superoxide dismutase, alpha-tocopherol, and desferrioxamine; however, glutathione, catalase, and selenium were not effective in preventing lipid peroxidation. Miura et al. ( 64) reported in vitr o inactivation of membrane enzymes Na/K-ATPase and Ca-ATPase during lipid peroxidation in erythrocyte membranes by doxorubicin and this effect was preventable by trolox, a water-soluble form of vitamin E, and butylated hydroxytoluene.

Nephrotoxicity

Cisplatin is a drug that is active against many cancers; however, severe nephrotoxicity and neurotoxicity are dose-limiting side effects of this drug and may result in significant morbidity. Administration of cisplatin with pre- and posttreatment hydration and mannitol-induced diuresis lowers the concentration of cisplatin in the kidneys and reduces its nephrotoxicity. An alternative approach to protect against the side effects of cisplatin is provided by chemoprotectors. Selenium has been reported to reduce cisplatin-induced nephrotoxicity ( 4, 62) in addition to its well-known chemopreventive properties ( 22). Sodium selenite has been shown to protect rodents against cisplatin nephrotoxicity without reducing the drug's antitumor activity ( 4). Reactions between cisplatin and nucleophilic metabolites of selenite may be responsible for the protective effect of selenite against cisplatin nephrotoxicity ( 5). Vermeulen et al. ( 109) concluded that sodium selenite protected rodents against cisplatin-induced nephrotoxicity without influencing the systemic availability of cisplatin.

Sadzuka et al. ( 88, 89) demonstrated that cisplatin-induced nephrotoxicity was closely associated with an increase in lipid peroxidation and a decrease in the activity of enzymes that protect against lipid peroxidation. Pretreatment with alpha-tocopherol and glutathione significantly decreased the amount of lipid peroxides produced in the kidney by the administration of cisplatin ( 90). Sugihara et al. ( 104, 105) found that alpha-tocopherol prevented lipid peroxidation and nephrotoxicity induced by cisplatin in rodents. Bogin et al. ( 10) reported that pretreatment with a combination of cysteine and alpha-tocopherol is protective against the nephrotoxicity and biochemical changes induced by administration of cisplatin in rats.

Micronutrients and Antitumor vs. Tumorigenic Effects of Radiation/Chemotherapy

The mechanism of action of radiation therapy and some chemotherapeutic agents involves the generation of toxic oxygen free radicals. Supplementing patients with antioxidant micronutrients during therapy may potentially interfere with the antitumor effects of the treatment. However, many of the antioxidants have been found to prevent treatment toxicity without reducing the efficacy of radiation or chemotherapy. Furthermore, certain micronutrients have antitumor effects, inhibit cancer cell proliferation, and induce cancer cell differentiation.

Vitamin E inhibits growth and causes morphological changes in several tumor cell lines in tissue culture ( 21, 79). Animal studies and clinical trials have also shown chemopreventive ( 12, 51) and antineoplastic activities ( 43, 95) of vitamin E. A number of experimental studies further suggest that vitamin E can enhance the growth-inhibitory effect of various cancer treatment modalities such as radiation, chemotherapy, and hyperthermia ( 79). At some doses vitamin E enhanced the tumor killing by irradiation ( 49). Prasad et al. ( 80) observed growth-inhibitory effects of vitamin C alone, vitamin E alone, combination of vitamin C, vitamin E, beta-carotene, and 13-cis-retinoic acid, when SK-30 melanoma cells were exposed to these agents in vitro. Furthermore, ascorbic acid, alone or in combination with beta-carotene, vitamin E, and 13-cis-retinoic acid, enhanced the growth-inhibitory effect of cisplatin, dacarbazine, tamoxifen, and interferon-alpha 2b.

Certain micronutrients have cancer chemopreventive properties and thus may play a role in the prevention of radiation- and chemotherapy-induced cancers. Krishnaswamy et al. ( 53) observed 57% complete remission rate of oral preneoplastic lesions in 150 subjects given a multivitamin capsule containing vitamin A, riboflavin, zinc, and selenium twice weekly for 1 year. Satoh et al. ( 91) reported that induction of increased pulmonary metallothionein by zinc or bismuth compounds could prevent the development of lung cancer in mice receiving repeated injections of cisplatin and melphalan. Zinc aspartate administration potentiated the radioprotective effect of diltiazem in mice given lethal dose of radiation ( 26). Combination of zinc aspartate with amifostine, an antioxidant compound, conferred protection against lethal effects of radiation as well as against the development of radiation-induced lymphomas in mice ( 27).

Oral administration of vitamins A and E in conjunction with FEMTX (fluorouracil, epirubicin, methotrexate) chemotherapy in patients with unresectable or meta-static gastric cancer does not appear to reduce the antitumor activity of the chemotherapeutic agents ( 81). Glutathione administration protected rodents against renal and lethal toxicity of cisplatin, but did not interfere with the drug's antitumor activity ( 116). In small clinical studies, protective effects of reduced glutathione against renal toxicity of cisplatin ( 11, 72) without interfering with its antitumor activity ( 72) were reported. Di Re et al. ( 19) confirmed these results in a larger series of 40 patients with ovarian cancer treated with high-dose cisplatin and cyclophosphamide given with pre- and posttreatment glutathione protection showing significant protection against renal toxicity with no effect on antitumor activity.

Rouse et al. ( 84) hypothesized that intravenous glutamine protects liver cells from oxidant injury by increasing intracellular glutathione content, and supplemental oral glutamine would increase the therapeutic index of methotrexate by improving host tolerance through changes in glutathione metabolism. Provision of glutamine-rich diet to rats with implanted fibrosarcomas treated with methotrexate decreased tumor glutathione and increased antitumor effect of methotrexate, while maintaining or increasing host glutathione stores ( 85). Significantly decreased glutathione levels in tumor cells correlated with their susceptibility to methotrexate and tumor shrinkage in animals that received the combination of glutamine and methotrexate. Thus, oral glutamine supplementation enhanced the sensitivity of the tumor cells while protecting the normal cells from the effects of methotrexate chemotherapy.

However, zinc administration has been shown to interfere with antitumor activity of cisplatin by increasing its detoxification through increased metallothionein synthesis ( 92). In C3H mice inoculated with bladder tumor (MBT-2), cisplatin and zinc sulfate were administered and reduction in both renal toxicity and antitumor activity of cisplatin was observed ( 93).

Pharmaceutical Compounds in the Prevention of Radiation and Chemotherapy Toxicities

Pharmaceutical compounds have been available for the prevention and treatment of various chemotherapy and radiation therapy toxicities and this area remains to be an active area of research. Prevention of cisplatin nephrotoxicity has been studied using multiple pharmaceutical agents including thiosulfate, calcium channel blockers, bismuth, glycine, cimetidine, and probenecid ( 62). Floersheim ( 26) reported protection of mice against lethal dose of radiation by diltiazem, as well as other calcium channel blockers such as nifedipine and nimodipine. Synergistic effects occurred by combining diltiazem with zinc aspartate, dimethyl sulfoxide, and nifedipine. In another study Floersheim et al. ( 27) found that small doses of zinc aspartate and amifostine provided additive protection against radiation lethality in mice. George et al. ( 35) have shown that pretreatment with 5-hydroxy-L-tryptophan ( 5-HTP) and 2-aminoethyl isothiuronium bromide hydrobromide (AET) combination prior to total body irradiation protected the mice against radiation-induced oligospermia and infertility. Somani et al. ( 97) observed increased creatinine and depletion of renal glutathione in rats given cisplatin and prevention of renal toxicity and glutathione depletion by simultaneous administration of diethylthiocarbamate. Crawford et al. ( 17) found that filgrastim (r-metHuG-CSF) affords prevention of oral mucositis in patients with small-cell lung cancer receiving chemotherapy.

Several sulfur-based nucleophilic agents, such as sodium thiosulfate ( 75), diethyldithiocarbamate ( 9), and amifostine ( 115), have been shown to reduce cisplatin-induced nephrotoxicity in animals. Amifostine has also been found to be protective against cisplatin-induced neuropathy ( 37, 66). However, these chemoprotectors also have intrinsic toxicity ( 83) and lack selectivity and reduce antitumor activity as well ( 1). Sodium thiosulfate not only reduces the nephrotoxicity but also the antitumor activity of cisplatin ( 1) by reacting chemically with cisplatin, forming a biologically inactive product ( 38) and reducing levels of active cisplatin in plasma ( 48).

The phosphorothioate, amifostine, has recently been approved for clinical use in the prevention of cisplatin toxicity. Currently its use in the prevention of radiation toxicity and toxicities of other chemotherapeutic agents is under investigation. The usefulness of phosphorothioates is limited by their toxicity, and it has been proposed that combining other agents with phosphorothioates may improve their efficacy and/ or lower their toxicity ( 113). Because zinc aspartate and combination of zinc aspartate with amifostine have shown better protective effects for normal tissue compared to tumor tissue ( 28-30) further clinical studies should test low-dose amifostine and zinc combination to determine if radiation protection can be achieved without the side effects of high-dose amifostine.

Dexrazoxane, a cyclic derivative of EDTA that readily penetrates cell membranes and converted intracellularly to a ring-opened chelating agent that interferes with iron-mediated free radical generation, has recently been approved for the prevention of doxorubicin-induced cardiomyopathy. Another chemoprotectant antioxidant compound in clinical use is mesna, which is used for the prevention of hemorrhagic cystitis associated with ifosfamide.

Hamers et al. ( 41) found that pretreatment with reduced glutathione protected rats against cisplatin-induced neuropathy without interfering with its antitumor activity. In this animal model neuropeptide ORG2766 and a calcium channel blocker nimodipine were also found to be effective in preventing cisplatin-induced neuropathy ( 18, 42). A clinical study confirmed the neuroprotective effect of ORG2766 in a clinical study ( 36). McGinness et al. ( 60) reported a protective effect of superoxide dismutase (orgotein) administration against cisplatin nephrotoxicity. Metallothionein induction by bismuth subnitrate has been reported to prevent cisplatin and doxorubicin toxicity ( 93). However, Sadzuka et al. found no protective effect by bismuth subnitrate in their experiments ( 90).

Storm et al. ( 102) found that mice were protected from toxic cellular effects of radiation when they were fed a diet containing 2% squalene prior to and after receiving a lethal dose of whole-body radiation. Irradiated mice fed squalene had significantly higher white cell and lymphocyte counts, better jejunal histologic picture, and longer survival compared to the control group.

Conclusions

Micronutrient supplementation may prevent adverse effects of cancer chemotherapy and radiation therapy without interfering with their antitumor effects. This protection may result in lower treatment-associated morbidity and mortality and better quality of life for cancer patients. There may even be potentiation of the antineoplastic effect of radiation and chemotherapy by micronutrients, which may lead to increased tumor responsiveness to treatments. Furthermore, micronutrients lack intrinsic toxicity, which is a major problem with some of the pharmaceutical compounds approved for clinical use as toxicity preventive agents. However, currently there are insufficient clinical data to support the use of micronutrients as adjunct to radiation or chemotherapy. Future clinical intervention trials should investigate the potential benefits and risks of micronutrient supplementation during cancer therapy.

Acknowledgment

I would like to thank Dr. Ananda Prasad for reviewing the manuscript.

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