Should patients take or avoid antioxidant supplements during anticancer therapy? An evidence-based review

Current Oncology

Volumn 12, Issue 2, 2005, Pages 44-54

  Sagar, Stephen M ^a,b  

^a JURAVINSKI CANCER CENTRE   (Canada)

^b MCMASTER UNIVERSITY   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA TOCOPHEROL; AMIFOSTINE; ANTIOXIDANT; ASCORBIC ACID; BETA CAROTENE; LYCOPENE; MESNA; PENTOXIFYLLINE; RETINOL; THIOCTIC ACID;

ANTIOXIDANT ACTIVITY; BIOLOGICAL ACTIVITY; CANCER CHEMOTHERAPY; CANCER CONTROL; CANCER INHIBITION; CANCER RESEARCH; DIET SUPPLEMENTATION; DOSE RESPONSE; DRUG EFFICACY; DRUG EXCRETION; DRUG METABOLISM; DRUG TOLERABILITY; HUMAN; NONHUMAN; PROSTATE CANCER; REVIEW; WOUND HEALING;

EID: 23644453445     PISSN: None     EISSN: 17187729     Source Type: Journal    
DOI: None     Document Type: Review

References (184)

1. Halliwell B. The antioxidant paradox. Lancet 2000;355: 1179-80.
2. Ricciarelli R, Zingg JM, Azzi A. Vitamin E: protective role of a Janus molecule. FASEB J 2001;15:2314-25.
3. Kumar B, Jha MN, Cole WC, Bedford JS, Prasad KN. D-α-Tocopheryl succinate (vitamin E) enhances radiation-induced chromosomal damage levels in human cancer cells, but reduces it in normal cells. J Am Coll Nutr 2002;21:339-43.
4. Schwartz JL. The dual roles of nutrients as antioxidants and prooxidants: their effects on tumor cell growth. J Nutr 1996;126(suppl):1221S-7S.
5. Salganik RI. The benefits and hazards of antioxidants: controlling apoptosis and other protective mechanisms in cancer patients and the human population. J Am Coll Nutr 2001;20(suppl):473S-5S.
6. Prasad KN, Cole WC, Kumar B. Pros and cons of antioxidant use during radiation therapy. Cancer Treat Rev 2002;28:79-91.
7. Krinsky N. Antioxidant functions of carotenoids. Free Radic Biol Med 1989;7:617-35.
8. Zhang LX, Cooney RV, Bertram JS. Carotenoids up-regulate connexin-43 gene expression independent of their provitamin A or antioxidant properties. Cancer Res 1992;52:5707-12.
9. Hazuka MB, Edwards-Prasad J, Newman F. Beta-carotene induces morphological differentiation and decreases adenylate cyclase activity in melanoma cells in culture. J Am Coll Nutr 1990;9:143-9.
10. Schwartz JL. Molecular and biochemical controls of tumor growth following treatment with carotenoids and tocopherols. In: Prasad KN, Santamaria L, Williams RM, eds. Nutrients in Cancer Prevention and Treatment. Totowa, NJ: Humana Press;1995: 287-316.
11. Agarwal S, Rao AV. Tomato lycopene and its role in human health and chronic diseases. CMAJ 2000;163:739-44.
12. Gann PH, Ma J, Giovannucci E, Willett W, et al. Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis. Cancer Res 1999;59:1225-30.
13. Heber D, Lu QY, Go VL. Role of tomatoes, tomato products and lycopene in cancer prevention. Adv Exp Med Biol 2001;492:29-37.
14. Pohar KS, Gong MC, Bahnson R, Miller EC, Clinton SK. Tomatoes, lycopene and prostate cancer: a clinician's guide for counseling those at risk for prostate cancer. World J Urol 2003;21:9-14.
15. Pathak SK, Sharma RA, Mellon JK. Chemoprevention of prostate cancer by diet-derived antioxidant agents and hormonal manipulation. Int J Oncol 2003;22:5-13.
16. Giovannucci E, Rimm EB, Liu Y, Stampfer MJ, Willett WC. A prospective study of tomato products, lycopene, and prostate cancer risk. J Natl Cancer Inst 2002;94:391-8.
17. Rossinow J, Balajee AS, Gewanter RM, et al. Dietary supplements and radiation therapy: effects of lycopene and vitamin E on prostate cancer cells (abstract). Int J Radiat Oncol Biol Phys 2003;57(suppl):S72.
18. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330:1029-35.
19. Omenn GS, Goodman GE, Thornquist MD, et al. Risk factors for lung cancer and for intervention effects in CARET, the β-Carotene and Retinol Efficacy Trial. J Natl Cancer Inst 1996;88:1550-9.
20. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334:1150-5.
21. Epstein KR. The role of carotenoids on the risk of lung cancer. Semin Oncol 2003;30:86-93.
22. Neuhouser ML, Patterson RE, Thornquist MD, Omenn GS, King IB, Goodman GE. Fruits and vegetables are associated with lower lung cancer risk only in the placebo arm of the β-Carotene and Retinol Efficacy Trial (CARET). Cancer Epidemiol Biomarkers Prev 2003;12:350-8.
23. Huttunen JK. Why did antioxidants not protect against lung cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study? IARC Sci Publ 1996;136:63-5.
24. Gopalakrishna R, Gundimeda U, Chen Z. Vitamin E succinate inhibits protein kinase C: correlation with its unique inhibitory effects on cell growth and transformation. In: Prasad KN, Santamaria L, Williams JH, eds. Nutrients in Cancer Prevention and Treatment. Totowa, NJ: Humana Press;1995: 21-37.
25. Gunawardena K, Murray DK, Meikle AW. Vitamin E and other antioxidants inhibit human prostate cancer cells through apoptosis. Prostate 2000;44:287-95.
26. Israel K, Yu W, Sanders BG. Vitamin E succinate induces apoptosis in human prostate cancer cells: role for fas in vitamin E succinate-triggered apoptosis. Nutr Cancer 2000;36:90-100.
27. Jha MN, Bedford JS, Cole WC. Vitamin E (D-α tocopheryl succinate) decreases mitotic accumulation in γ-irradiated human tumor, but not in normal cells. Nutr Cancer 1999;35:189-94.
28. Kline K, Yu W, Zhao B. Vitamin E succinate: mechanisms of action as tumor growth inhibitor. In: Prasad K, Santamaria L, Williams R, eds. Nutrients in Cancer Prevention and Treatment. Totowa, NJ: Humana Press;1995: 39-55.
29. Londer HM, Myers CE. Radioprotective effects of vitamin E (abstract). Am J Clin Nutr 1978;31:705a.
30. Mahoney C, Azzi A. Vitamin E inhibits protein kinase C activity. Biochem Biophys Res Commun 1988;154:694-7.
31. Malafa MP, Neitzel LT. Vitamin E succinate promotes breast cancer dormancy and inhibits VEGF gene expression. In: Proceedings of the International Congress on Frontiers of Pharmacology and Therapeutics in 21st Century; 1-4 December 1999; New Delhi, India. 1999: 15-19.
32. Malick MA, Roy RM, Sternberg J. Effect of vitamin E on post-irradiation death in mice. Experientia 1978;34:1216-17.
33. Mutlu-Turkoglu U, Erbil Y, Oztezcan S, Olgae V, Toker G, Uysal M. The effect of selenium and/or vitamin E treatments on radiation induced intestinal injury in rats. Life Sci 2000;66: 1905-13.
34. Pace A, Savarese A, Picardo M, et al. Neuroprotective effect of vitamin E supplementation in patients treated with cisplatin chemotherapy. J Clin Oncol 2003;21:927-31.
35. Prasad KN, Edwards-Prasad J. Effect of tocopherol (vitamin E) acid succinate on morphological alterations and growth inhibition in melanoma cells in culture. Cancer Res 1982;42:550-5.
36. Prasad KN, Cohrs RJ, Sharma OK. Decreased expressions of C-myc and H-ras oncogenes in vitamin E succinate induced morphologically differentiated murine B-16 melanoma cells in culture. Biochem Cell Biology 1990;68:1250-5.
37. Yu W, Israel K, Liao QY, Aldaz CM, Sanders BG, Kline K. Vitamin E succinate (VES) induces fas sensitivity in human breast cancer cells: role for MR 43,000 fas in VES-triggered apoptosis. Cancer Res 1999;59:953-61.
38. Turley J, Ruscetti F, Kim SJ. Vitamin E succinate inhibits proliferation of BT-20 human breast cancer cells: increased binding of cyclic AMP negatively regulates E2F transactivation activity. Cancer Res 1997;57:2668-75.
39. Delanian S. Striking regression of radiation-induced fibrosis by a combination of pentoxifylline and tocopherol. Br J Radiol 1998;71:892-4.
40. Turley JM, Fu T, Ruscetti FW, Mikovits JA. Vitamin E succinate induces fas-mediated apoptosis in estrogen receptor-negative human breast cancer cells. Cancer Res 1997;57:881-90.
41. Kennedy AR, Krinsky NI. Effects of retinoids, beta-carotene, and canthaxanthin on UV- and X-ray-induced transformation of C3H10T1/2 cells in vitro. Nutr Cancer 1994;22:219-32.
42. Prasad KN, Kumar A, Kochupillai V, Cole WC. High doses of multiple antioxidant vitamins: essential ingredients in improving the efficacy of standard cancer therapy. J Am Coll Nutr 1999;18:13-25.
43. Prasad KN, Cole WC, Kumar B, Prasad KC. Scientific rationale for using high-dose multiple micronutrients as an adjunct to standard and experimental cancer therapies. J Am Coll Nutr 2001;20(suppl):473S-5S.
44. Karbownik M, Reiter RJ. Antioxidative effects of melatonin in protection against cellular damage caused by ionizing radiation. Proc Soc Exp Biol Med 2000;225:9-22.
45. Pinnell SR. Cutaneous photodamage, oxidative stress, and topical antioxidant protection. J Am Acad Dermatol 2003;48:1-19.
46. Sieja K. Protective role of selenium against the toxicity of multi-drug chemotherapy in patients with ovarian cancer. Pharmazie 2000;55:958-9.
47. Hu YJ, Chen Y, Zhang YQ, et al. The protective role of selenium on the toxicity of cisplatin-contained chemotherapy regimen in cancer patients. Biol Trace Elem Res 1997;56:331-41.
48. Jones K, Hughes K, Mischley L, McKenna DJ. Coenzyme Q-10: efficacy, safety, and use. Altern Ther Health Med 2002;8:42-56.
49. Hodges S, Hertz N, Lockwood K, Lister R. CoQ10: could it have a role in cancer management? Biofactors 1999;9:365-70.
50. Tamimi RM, Lagiou P, Adami HO, Trichopoulos D. Prospects for chemoprevention of cancer. J Intern Med 2002;251: 286-300.
51. Kakizoe T. Chemoprevention of cancer-focusing on clinical trials. Jpn J Clin Oncol 2003;33:421-42.
52. Raich PC, Lu J, Thompson HJ, Combs GF Jr. Selenium in cancer prevention: clinical issues and implications. Cancer Invest 2001;19:540-53.
53. Nishino H, Murakosh M, Ii T, et al. Carotenoids in cancer chemoprevention. Cancer Metastasis Rev 2002;21:257-64.
54. Singh DK, Lippman SM. Cancer chemoprevention. Part 1: Retinoids and carotenoids and other classic antioxidants. Oncology 1998;12:1643-53.
55. Malila N, Virtamo J, Virtanen M, Pietinen P, Albanes D, Teppo L. Dietary and serum alpha-tocopherol, beta-carotene and retinol, and risk for colorectal cancer in male smokers. Eur J Clin Nutr 2002;56:615-21.
56. Sato R, Helzlsouer KJ, Alberg AJ, Hoffman SC, Norkus EP, Comstock GW. Prospective study of carotenoids, tocopherols, and retinoid concentrations and the risk of breast cancer. Cancer Epidemiol Biomarkers Prev 2002;11:451-7.
57. Rautalahti MT, Virtamo JR, Taylor PR, et al. The effects of supplementation with alpha-tocopherol and beta-carotene on the incidence and mortality of carcinoma of the pancreas in a randomized, controlled trial. Cancer 1999;86:37-42.
58. Longnecker MP, Newcomb PA, Mittendorf R, Greenberg ER, Willett WC. Intake of carrots, spinach, and supplements containing vitamin A in relation to risk of breast cancer. Cancer Epidemiol Biomarkers Prev 1997;6:887-92.
59. La Vecchia C, Altieri A, Tavani A. Vegetables, fruit, antioxidants and cancer: a review of Italian studies. Eur J Nutr 2001;40:261-7.
60. Ito Y, Suzuki K, Suzuki S, Sasaki R, Otani M, Aoki K. Serum antioxidants and subsequent mortality rates of all causes or cancer among rural Japanese inhabitants. Int J Vitam Nutr Res 2002;72:237-50.
61. Rowe PM. Beta-carotene takes a collective beating. Lancet 1996;347:249.
62. Albanes D, Heinonen OP, Taylor PR, et al. Alpha-tocopherol and beta-carotene supplements and lung cancer incidence in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study: effects of base-line characteristics and study compliance. J Natl Cancer Inst 1996;88:1560-70.
63. Albanes D, Heinonen OP, Huttunen JK, et al. Effects of alpha-tocopherol and beta-carotene supplements on cancer incidence in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study. Am J Clin Nutr 1995;62(suppl):1427S-30S.
64. Greenwald P, McDonald SS. The beta-carotene story. Adv Exp Med Biol 2001;492:219-31.
65. Mayne ST, Handelman GJ, Beecher G. Beta-carotene and lung cancer promotion in heavy smokers-a plausible relationship? J Natl Cancer Inst 1996;88:1513-15.
66. Wang XD, Russell RM. Procarcinogenic and anticarcinogenic effects of beta-carotene. Nutr Rev 1999;57:263-72.
67. Woutersen RA, Wolterbeek AP, Appel MJ, van den Berg H, Goldbohm RA, Feron VJ. Safety evaluation of synthetic beta-carotene. Crit Rev Toxicol 1999;29:515-42.
68. Rehman A, Collis CS, Yang M. The effects of iron and vitamin C co-supplementation on oxidative damage to DNA in healthy volunteers. Biochem Biophys Res Commun 1998;246: 293-8.
69. Rehman A, Bourne LC, Halliwell B, Rice-Evans CA. Tomato consumption modulates oxidative DNA damage in humans. Biochem Biophys Res Commun 1999;262:828-31.
70. Deng XS, Tuo J, Poulsen HE, Loft S. Prevention of oxidative DNA damage in rats by Brussels sprouts. Free Radic Res 1998;25:323-33.
71. Prieme H, Loft S, Nyyssonen K, Salonen JT, Poulsen HT. No effect of supplementation with vitamin E, ascorbic acid or coenzyme Q-10 on oxidative DNA damage estimated by 8-oxo-7,8-dihydro-2′-deoxyguanosine excretion in smokers. Am J Clin Nutr 1997;65:503-7.
72. Beatty ER, England TG, Geissler CA, Aruoma OI, Halliwell B. Effects of antioxidant vitamin supplementation on markers of DNA damage and plasma antioxidants (abstract). Proc Nutr Soc 1999;58:44A.
73. Podmore ID, Griffiths HR, Herbert KE, Mistry N, Mistry P, Lunec J. Vitamin C exhibits pro-oxidant properties. Nature 1998;392:559.
74. Fraga CG, Motchnik PA, Wyrobek AJ, Rempel DM, Ames BN. Smoking and low antioxidant levels increase oxidative damage to sperm DNA. Mutat Res 1996;351:199-203.
75. Cole WC, Prasad KN. Contrasting effects of vitamins as modulators of apoptosis in cancer cells and normal cells: a review. Nutr Cancer 1997;29:97-103.
76. Kajdaniuk D, Marek B, Kos-Kudla B. Influence of adjuvant chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil on plasma melatonin and chosen hormones in breast cancer premenopausal patients. J Clin Pharm Ther 2001;26:297-301.
77. Formelli F, Cleris L. Synthetic retinoid fenretinide is effective against a human ovarian cancer xenograft and potentiates cisplatin activity. Cancer Res 1993;53:5374-6.
78. Chinery R, Brockman J, Peeler M. Antioxidants enhance the cytotoxicity of chemotherapeutic agents in colorectal cancer: a p53-independent induction of p21WAF/CIP1 via C/EBPβ. Nat Med 1997;11:1233-41.
79. Seifter E, Rettura A, Padawar J. Vitamin A and beta-carotene as adjunctive therapy to tumor excision, radiation therapy and chemotherapy. In: Prasad KN, ed. Vitamins, Nutrition and Cancer. Basel: Karger; 1984.
80. Meyskens FL. Role of vitamin A and its derivatives in the treatment of human cancer. In: Prasad KN, Santamaria L, Williams RM, eds. Nutrients in Cancer Prevention and Treatment. Totowa, NJ: Humana Press;1995: 349-62.
81. Lippman SM, Parkinson DR, Itri LM, et al. 13-cis Retinoic acid plus interferon cc-2a: highly active systemic therapy for squamous carcinoma of the cervix. J Natl Cancer Inst 1995;84: 241-5.
82. Hanck AB. Vitamin C and cancer. Prog Clin Biol Res 1988;259:307-20.
83. Cameron E, Pauling L, Leibowitz B. Ascorbic acid and cancer: a review. Cancer Res 1979;39:663-81.
84. Garewal H. Antioxidants in oral cancer prevention. Am J Clin Nutr 1995;62(suppl):1410S-16S.
85. Garewal HS, Schantz S. Emerging role of beta-carotene and antioxidant nutrients in prevention of oral cancer. Arch Otolaryngol Head Neck Surg 1995;121:141-4.
86. Garewal H. Beta-carotene and antioxidant nutrients in oral cancer prevention. In: Prasad KN, Santamaria L, Williams JH, eds. Nutrients in Cancer Prevention and Treatment. Totowa, NJ: Humana Press;1995: 235-47.
87. Garewal HS, Katz RV, Meyskens F, et al. Beta-carotene produces sustained remissions in patients with oral leukoplakia: results of a multicenter prospective trial. Arch Otolaryngol Head Neck Surg 1999;125:1305-10.
88. Witenberg B, Kletter Y, Kalir HH. Ascorbic acid inhibits apoptosis induced by X-irradiation in HL60 myeloid leukemia cells. Radiat Res 1999;152:468-78.
89. Sakamoto K, Sakka M. Reduced effect of irradiation on normal and malignant cells irradiated in vivo in mice pretreated with vitamin E. Br J Radiol 1973;46:538-40.
90. Park CH. Vitamin C in leukemia and preleukemia cell growth. Prog Clin Biol Res 1988;259:321-30.
91. Prasad KN, Kumar R. Effect of individual antioxidant vitamins alone and in combination on growth and differentiation of human non-tumorigenic and tumorigenic parotid acinar cells in culture. Nutr Cancer 1996;26:11-19.
92. Prasad KN, Hernandez C, Edwards-Prasad J. Modification of the effect of tamoxifen, cisplatin, DTIC, and interferon-A2B on human melanoma cells in culture by a mixture of vitamins. Nutr Cancer 1994;22:233-45.
93. Gago-Dominguez M, Castelao JE, Yuan JM, Ross RK, Yu MC. Lipid peroxidation: a novel and unifying concept of the etiology of renal cell carcinoma. Cancer Causes Control 2002;13:287-93.
94. Neuzil J, Svensson I, Weber T. Alpha-tocopheryl succinate-induced apoptosis in Jurcat T cells involves capase-3 activation, and both lysosomal and mitochondrial destabilisation. FEBS Lett 1999;445:295-300.
95. Nakamura T, Goto M, Matsumoto A, Tanaka I. Inhibition of NF-K B transcriptional activity by alpha-tocopheryl succinate. Biofactors 1998;7:21-30.
96. Liede KE, Alfthan G, Hietanen JH. Beta-carotene concentration in buccal mucosal cells with and without dysplastic oral leukoplakia after long-term beta-carotene supplementation in male smokers. Eur J Clin Nutr 1998;52:872-6.
97. Agus DB, Vera JC, Golde DW. Stromal cell oxidation: a mechanism by which tumors obtain vitamin C. Cancer Res 1999;59: 4555-8.
98. Piyathilake CJ, Bell WC, Johanning JL. The accumulation of ascorbic acid by squamous carcinomas of the lung and larynx is associated with global methylation of DNA. Cancer 2000;89: 171-6.
99. Picardo M, Grammatico P, Roccella F. Imbalance in the anti-oxidant pool in melanoma cells and normal melanocytes from patients with melanoma. J Invest Dermatol 1996;107:322-6.
100. Langemann H, Torhorst J, Kabiersch A. Quantitative determination of water- and lipid-soluble antioxidants in neoplastic and non-neoplastic human breast tissue. Int J Cancer 1989;43: 1169-73.
101. Ladas EJ, Jacobson JS, Kennedy DD, Teel K, Fleischauer A, Kelly KM. Antioxidants and cancer therapy: a systematic review. J Clin Oncol 2004;22:517-28.
102. Jonas CR, Puckett AB, Jones DP, et al. Plasma antioxidant status after high-dose chemotherapy: a randomized trial of parenteral nutrition in bone marrow transplantation patients. Am J Clin Nutr 2000;72:181-9.
103. Norman HA, Butrum RR, Feldman E, et al. The role of dietary supplements during cancer therapy. J Nutr 2003;133: 3794S-9S.
104. Faber M, Coudray C, Hida H, Mousseau M, Favier A. Lipid peroxidation products, and vitamin and trace element status in patients with cancer before and after chemotherapy, including adriamycin. A preliminary study. Biol Trace Elem Res 1995;47:117-23.
105. United States, Institute of Medicine, Food and Nutrition Board. Introduction to dietary reference intakes. In: Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: National Academy Press;2002: 21-34.
106. Tamayo C, Richardson MA. Vitamin C as a cancer treatment: state of the science and recommendations for research. Altern Ther Health Med 2003;9:94-101.
107. Hoffer LJ. Proof versus plausibility: rules of engagement for the struggle to evaluate alternative cancer therapies. CMAJ 2001;164:351-3.
108. Flagg EW, Coates RJ, Greenberg RS. Epidemiologic studies of antioxidants and cancer in humans. J Am Coll Nutr 1995;14:419-27.
109. Goodman MT, Kiviat N, McDuffie K, et al. The association of plasma micronutrients with the risk of cervical dysplasia in Hawaii. Cancer Epidemiol Biomarkers Prev 1998;7:537-44.
110. Jacobs EJ, Connell CJ, Patel AV, et al. Vitamin C and vitamin E supplement use and colorectal cancer mortality in a large American Cancer Society cohort. Cancer Epidemiol Biomarkers Prev 2001;10:17-23.
111. Lee IM. Antioxidant vitamins in the prevention of cancer. Proc Assoc Am Physicians 1999;111:10-15.
112. Machlin LJ. Critical assessment of the epidemiological data concerning the impact of antioxidant nutrients on cancer and cardiovascular disease. Crit Rev Food Sci Nutr 1995;35:41-50.
113. Mackerras D, Irwig L, Simpson JM, et al. Randomized double-blind trial of beta-carotene and vitamin C in women with minor cervical abnormalities. Br J Cancer 1999;79:1448-53.
114. Malila N, Virtamo J, Virtanen M, Albanes D, Tangrea JA, Huttunen JK. The effect of alpha-tocopherol and beta-carotene supplementation on colorectal adenomas in middle-aged male smokers. Cancer Epidemiol Biomarkers Prev 1999;8:489-93.
115. Zhang SM, Calle EE, Petrelli JM, Jacobs EJ, Thun MJ. Vitamin supplement use and fatal non-Hodgkin's lymphoma among U.S. men and women. Am J Epidemiol 2001;153:1064-70.
116. Lee SH, Oe T, Blair IA. Vitamin C-induced decomposition of lipid hydroperoxides to endogenous genotoxins. Science 2001;292:2083-6.
117. Jacobs EJ, Henion AK, Briggs PJ, et al. Vitamin C and vitamin E supplement use and bladder cancer mortality in a large cohort of U.S. men and women. Am J Epidemiol 2002;156:1002-10.
118. Gonzalez MJ, Miranda-Massari JR, Mora EM, et al. Orthomolecular oncology: a mechanistic view of intravenous ascorbate's chemotherapeutic activity. P R Health Sci J 2002;21:39-41.
119. Earth TJ, Zoller J, Kubler A, Born IA, Osswald H. Redifferentiation of oral dysplastic mucosa by the application of the antioxidants beta-carotene, alpha-tocopherol and vitamin C. Int J Vitam Nutr Res 1997;67:368-76.
120. Lee KW, Lee HJ, Kang KS, Lee CY. Preventive effects of vitamin C on carcinogenesis. Lancet 2002;359:172.
121. Luben R, Khaw KT, Welch A, et al. Plasma vitamin C, cancer mortality and incidence in men and women: a prospective study. IARC Sci Publ 2002;156:117-18.
122. Correa P, Malcom G, Schmidt B, et al. Review article: antioxidant micronutrients and gastric cancer. Aliment Pharmacol Ther 1998;1:73-82.
123. Terry P, Lagergren J, Ye W, Nyren O, Wolk A. Antioxidants and cancers of the esophagus and gastric cardia. Int J Cancer 2000;87:750-4.
124. Voorrips LE, Goldbohm RA, Brants HA, et al. A prospective cohort study on antioxidant and folate intake and male lung cancer risk. Cancer Epidemiol Biomarkers Prev 2000;9:357-65.
125. Jamison JM, Gilloteaux J, Taper HS, Calderon PB, Summers JL. Autoschizis: a novel cell death. Biochem Pharmacol 2002;63:1773-83.
126. Munoz N, Vivas J, Buiatti E, Kato I, Oliver W. Chemoprevention trial on precancerous lesions of the stomach in Venezuela: summary of study design and baseline data. IARC Sci Publ 1996;139:125-33.
127. Ekstrom AM, Serafini M, Nyren O, Hansson LE, Ye W, Wolk A. Dietary antioxidant intake and the risk of cardia cancer and noncardia cancer of the intestinal and diffuse types: a population-based case-control study in Sweden. Int J Cancer 2000;87:133-40.
128. You WC, Chang YS, Heinrich J, et al. An intervention trial to inhibit the progression of precancerous gastric lesions: compliance, serum micronutrients and 5-allyl cysteine levels, and toxicity. Eur J Cancer Prev 2001;10:257-63.
129. White KL, Chalmers DM, Martin IG, et al. Dietary antioxidants and DNA damage in patients on long-term acid-suppression therapy: a randomized controlled study. Br J Nutr 2002;88:265-71.
130. Creagan ET, Moertel CG, O'Fallon JR. Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. A controlled trial. N Engl J Med 1979;301: 687-90.
131. Moertel CG, Fleming TR, Creagan ET. High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison. N Engl J Med 1985;312:137-41.
132. Labriola D, Livingston R. Possible interactions between dietary antioxidants and chemotherapy. Oncology (Huntingt) 1999;13:1003-8.
133. Capizzi RL, Oster W. Chemoprotective and radioprotective effects of amifostine: an update of clinical trials. Int J Hematol 2000;72:425-35.
134. Mantovani G, Maccio A, Madeddu C, et al. Reactive oxygen species, antioxidant mechanisms and serum cytokine levels in cancer patients: impact of an antioxidant treatment. J Cell Mol Med 2002;6:570-82.
135. Orditura M, De Vita F, Roscigno A, et al. Amifostine: a selective cytoprotective agent of normal tissues from chemo-radiotherapy induced cytotoxicity. Oncol Rep 1999;6:1357-62.
136. Ormstad K, Orrenius S, Lastbom T, et al. Pharmacokinetics and metabolism of sodium 2-mercaptoethanesulfonate in the rat. Cancer Res 1983;43:333-8.
137. Shacter E, Williams JA, Hinson RM, Senturker S, Lee YJ. Oxidative stress interferes with cancer chemotherapy: inhibition of lymphoma cell apoptosis and phagocytosis. Blood 2000;96:307-13.
138. Drisko JA, Chapman J, Hunter VJ. The use of antioxidant therapies during chemotherapy. Gynecol Oncol 2003;88:434-9.
139. Senturker S, Tschirret-Guth R, Morrow J, Levine R, Schacter E. Induction of apoptosis by chemotherapeutic drugs without generation of reactive oxygen species. Arch Biochem Biophys 2002;397:262-72.
140. Henner WD, Peters WP, Eden JP. Pharmacokinetics and immediate effects of high-dose carmustine in man. Cancer Treat Rep 1986;70:877-80.
141. Macdonald JS, Haller DG, Mayer RJ, eds. Manual of Oncologic Therapeutics. Philadelphia: JB Lipincott;1995: 80-135.
142. Lenzhofer R, Ganzinger U, Rameis H. Acute cardiac toxicity in patients after doxorubicin treatment and the effect of combined tocopherol and nifedipine pretreatment. J Cancer Res Clin Oncol 1983;106:143-7.
143. Chabner BA, Longo DL. Cancer Chemotherapy and Biotherapy. 3rd ed. Philadelphia: Lippincott Williams and Wilkins; 2001.
144. Connors TA. Mechanisms of clinical drug resistance. Biochem Pharmacol 1974;23(suppl):89-100.
145. David-Cordonnier MH, Laine W, Joubert A, et al. Covalent binding to glutathione of the DNA-alkylating antitumor agent, S23906-1. Eur J Biochem 2003;270:2848-59.
146. Tew KD. Glutathione-associated enzymes in anticancer drug resistance. Cancer Res 1994;54:4313-20.
147. Wilhelm D, Bender K, Knebel A, Angel P. The level of intracellular glutathione is a key regulator for the induction of stress-activated signal transduction pathways including jun N-terminal protein kinases and p38 kinase by alkylating agents. Mol Cell Biol 1997;17:4792-800.
148. Calautti P, Moschini G, Stievano BM. Serum selenium levels in malignant lymphoproliferative diseases. Scand J Haematol 1980;24:63-6.
149. Church SL, Grant JW, Ridnour LA. Increased manganese oxide dismutase expression suppresses the malignant phenotype of human melanoma cells. Proc Natl Acad Sci U S A 1993;90: 3113-17.
150. De Flora S, D'Agostini F, Masiello L. Synergism between N-acetylcysteine and doxorabicin in the prevention of tumorigenicity and metastasis in murine models. Int J Cancer 1996;67: 842-8.
151. Erhola M, Kellokumpu-Lehtinen P, Metsa-Ketela T. Effects of anthracyclin-based chemotherapy on total plasma antioxidant capacity in small cell lung cancer patients. Free Radic Biol Med 1996;21:383-90.
152. Srinavasan V, Jacobs AL, Simpson SA. Radioprotection by vitamin E. Effect on hepatic enzymes, delayed type hypersensitivity, and post-irradiation survival in mice. In: Meyskens F, Prasad K, eds. Modulation and Mediation of Cancer by Vitamins. Basel: Karger;1983: 119-31.
153. Delaney TF, Afridi N, Taghian AG. 13-cis-Retinoic acid with alpha-2a-interferon enhances radiation cytotoxicity in head and neck squamous cell carcinoma in vitro. Cancer Res 1996;56: 2277-80.
154. Saintot M, Astre C, Pujol H, Gerber M. Tumor progression and oxidant-antioxidant status. Carcinogenesis 1996;17: 1267-71.
155. Sarria A, Prasad KN. DL-alpha-tocopheryl succinate enhances the effect of gamma-irradiation on neuroblastoma cells in culture. Proc Soc Exp Biol Med 1984;175:88-92.
156. Blumenthal RD, Lew W, Reising A, et al. Antioxidant vitamins reduce normal tissue toxicity induced by radio-immunotherapy. Int J Cancer 2000;86:276-80.
157. O'Connor MK, Malone JF, Moriarty M. Radioprotective effect of vitamin C observed in Chinese hamster ovary cells. Br J Radiol 1977;50:587-91.
158. Ala-Ketola L, Varis R, Kiviniitty K. Effect of ascorbic acid on the survival of rats after whole body irradiation. Strahlentherapie 1974;148:643-4.
159. Okunieff P, Suit HD. Toxicity, radiation sensitivity modification, and combined drug effects of ascorbic acid with misonidazole in vivo on FSAII murine fibrosarcomas. J Natl Cancer Inst 1987;79:377-81.
160. Konopacka M, Widel M, Rzeszowska-Wolny J. Modifying effects of vitamins C, E and beta-carotene against gamma ray-induced DNA damage in mouse cells. Mutat Res 1998;417: 85-94.
161. Sun J, Chen Y, Li M. Role of antioxidant enzymes on ionizing radiation resistance. Free Radic Biol Med 1998;24:586-93.
162. Sinclair WK. Cysteamine: differential X-ray protective effect on Chinese hamster cells during the cell cycle. Science 1968;159:442-4.
163. Hirose K, Longo DL, Oppenheim JJ. Overexpression of mitochondrial manganese superoxide dismutase promotes the survival of tumor cells exposed to interleukin-1, tumor necrosis factor, selected anticancer drugs, and ionizing radiation. FASEB J 1993;7:361-8.
164. Motoori S, Mazima H, Ebara M. Overexpression of mitochondrial manganese superoxide dismutase protects against radiation-induced cell death in the human hepatocellular carcinoma cell line HLE. Cancer Res 2001;61:5382-8.
165. Urano M, Kuroda M, Reynolds R. Expression of manganese superoxide dismutase reduces tumor control radiation dose: gene radiotherapy. Cancer Res 1995;55:2490-3.
166. Tewfik FA, Tewfik HH, Riley EF. The influence of ascorbic acid on the growth of solid tumors in mice and on tumor control by X-irradiation. Int J Vitam Nutr Res 1982;23(suppl): 257-63.
167. Mills EE. The modifying effect of beta-carotene on radiation and chemotherapy induced oral mucositis. Br J Cancer 1988;57:416-17.
168. Wadleigh RG, Redman RS, Graham ML. Vitamin E in the treatment of chemotherapy-induced mucositis. Am J Med 1992;92:481-4.
169. Lippman SM, Parkinson DR, Itri LM, et al. 13-cis-Retinoic acid and interferon alpha-2a: effective combination therapy for advanced squamous carcinoma of the skin. J Natl Cancer Inst 1995;84:235-41.
170. Jaakkola K, Lahteenmaki P, Laakso J, Harju E, Tykka H, Mahlberg K. Treatment with antioxidant and other nutrients in combination with chemotherapy and irradiation in patients with small-cell lung cancer. Anticancer Res 1992;12:599-606.
171. Gedlicka C, Kornek GV, Scmid K, Scheithauer W. Amelioration of docetaxel/cisplatin induced polyneuropathy by alpha-lipoic acid. Ann Oncol 2003;14:339-40.
172. Ledee-Bataille N, Olivennes F, Lefaix JL, Chaouat G, Frydman R, Delanian S. Combined treatment by pentoxifylline and tocopherol for recipient women with a thin endometrium enrolled in an oocyte donation programme. Hum Reprod 2002;17:1249-53.
173. Delanian S, Porcher P, Balla-Mekias S, Lefaix JL. Randomized, placebo-controlled trial of combined pentoxifylline and tocopherol for regression of superficial radiation-induced fibrosis. J Clin Oncol 2003;21:2545-50.
174. United States, National Institutes of Health, National Library of Medicine. IH636 Grape seed extract in treating hardening of breast tissue in women who have undergone radiation therapy for early breast cancer [online clinical trials resource]. Bethesda: National Library of Medicine; 13 October 2004. [Available online at: www.clinicaltrials.gov/ct/show/ nct00041223; cited 27 May 2005]
175. Liu RH. Health benefits of fruit and vegetables are from additive and synergistic combinations of phytochemicals. Am J Clin Nutr 2003;78(suppl):517S- 20S.
176. Burstein HJ, Gelber S, Guadagnoli E. Use of alternative medicine by women with early-stage breast cancer. N Engl J Med 1999;340:1733-9.
177. VandeCreek L, Rogers E, Lester J. Use of alternative therapies among breast cancer outpatients compared with the general population. Altern Ther Health Med 1999;5:71-6.
178. Bjelavic G, Nikolova D, Simonetti RG, Gluud C. Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. Lancet 2004;364:1219-28.
179. Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37-46.
180. Spector R, Vesell ES. Which studies of therapy merit credence? Vitamin E and estrogen therapy as cautionary examples. J Clin Pharmacol 2002;42:955-62.
181. Seifried HE, McDonald SS, Anderson DE, Greenwald P, Milner JA. The antioxidant conundrum in cancer. Cancer Res 2003;63:4295-8.
182. Saver JL, Kalafut M. Combination therapies and the theoretical limits of evidence-based medicine. Neuroepidemiology 2001;20:57-64.
183. Torun M, Yardim S, Gonenc A, Sargin H, Menevse A, Simsek B. Serum beta-carotene, vitamin E, vitamin C and malondialdehyde levels in several types of cancer. J Clin Pharm Ther 1995;20:259-63.
184. Parthasarathy S, Khan-Merchant N, Penumetcha M, Khan BV, Santanam N. Did the antioxidant trials fail to validate the oxidation hypothesis? Curr Atheroscler Rep 2001;3:392-8.