CORRESPONDENCE Antioxidants in Cancer Therapy Kedar N. Prasad, William C. Cole Premier Micronutrient Corporation Antioxidant Research Institute, Novato, CA To the Editor: We read Bairati et al's1 article with interest. However, their conclusion–"However, this trial suggests that use of high doses of antioxidants as adjuvant therapy might compromise radiation treatment" is misleading and inaccurate for the reasons presented in this letter. This study1 began in 1994 when the results of a few studies pertinent to the trial were available. For example, Seifter2 reported that high doses of vitamin A and beta-carotene reduced the growth of adenocarcinoma of breast in mice and enhanced the effect of irradiation on tumor cells while protecting normal cells. Mills3 administered a high dose (100 mg/d) of beta-carotene to demonstrate that radiation-induced mucositis was reduced in human tumors without interfering with the efficacy of therapy. Bairati et al used only 30 mg/daily.1 It is not clear whether they used synthetic or natural form of beta-carotene. It should be noted, that it is too often assumed that the form of a particular antioxidant is not critical for obtaining the optimal result. For example, Kennedy et al showed that the natural form of beta-carotene was more effective in reducing radiation-induced damage than the synthetic form.4 The Bairati et al1 study has used a synthetic form of alpha-tocopherol. Prasad et al5 demonstrated that alpha-tocopheryl succinate (alpha-TS) was the most effective form of vitamin E in reducing proliferation rate and inducing cell lethality in melanoma cells in culture, while alpha tocopherol was ineffective. In 1994, it was also known that alpha-tocopherol protected both normal and cancer cells.6 In the Kumar et al article,7 a growth-inhibitory dose of alpha-TS and not of alpha-tocopherol was used. It has been shown that the synthetic form of vitamin E is absorbed by various organs in much lesser amounts in comparison with the natural form.8 Therefore, the selection of the synthetic form of alpha-tocopherol for protecting normal cells in the Bairati et al study was unfortunate. At this stage in vitamin E research, assuming that all forms of vitamin E—irrespective of dosage—may produce the same effect, is not correct. Additional data on antioxidants and cancer shows that the selection of antioxidants and the importance of their dosages to achieve optimal results are now available. For example, vitamin E alone can increase the risk of chemical-induced cancer in an animal model and vitamin C at lower doses can stimulate the growth of some cancer cells.6 Therefore, the increased rate of recurrence in the supplemented group was not an unexpected finding. Prasad et al6,9 have provided scientific, rational, and supporting data to show the importance of antioxidant form, dosage, and dose schedules. In particular, they show the importance of therapeutic doses (doses that reduce the growth of cancer cells) of multiple antioxidants and their derivatives (vitamin A, vitamin C, alpha-TS, and natural beta-carotene) rather than preventive doses of these agents. The Prasad et al reviews6,9 have emphasized importance of dose schedule, and have recommended daily administration of antioxidants at least 48 hours before irradiation. As a result, such a dose schedule may allow antioxidants to initiate damage in tumor cells, but not in normal cells before radiation therapy. Continuation of antioxidants after irradiation is important in order to reduce the rate of repair of radiation-induced damage in tumor cells, but not in normal cells. Maintenance doses of multiple antioxidants should be lower than those used in therapy, but higher than those used for cancer prevention study. After completion of radiation therapy, residual tumor cells may exist in varying number, and higher dose antioxidants may induce apoptosis in these cells directly or via stimulating immune function. We encourage radiation oncologists to initiate a clinical study with high-dose multiple dietary antioxidants according to the dosage and dose schedule described in previous reviews.6,9 Authors' Disclosures of Potential Conflicts of Interest Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required REFERENCES 1. Bairati I, Meyer F, Gélinas M, et al: Randomized trial of antioxidant vitamins to prevent acute adverse effects of radiation therapy in head and neck cancer patients. J Clin Oncol 23:5805-5813, 2005 2. Seifter E, Rettura A, Padawar J, et al: Vitamin A and ß-carotene as adjunctive therapy to tumor excision, radiation therapy and chemotherapy, in Prasad KN (ed): Vitamins, Nutrition and Cancer. Basel, Switzerland, Karger, 1984, pp 1-19 3. Mills EE: The modifying effect of beta-carotene on radiation and chemotherapy induced oral mucositis. Br J Cancer 57:416-417, 1988 4. 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 22:219-232, 1994 5. Prasad KN, Edwards-Prasad J: Effects of tocopherol (vitamin E) acid succinate on morphological alterations and growth inhibition in melanoma cells in culture. Cancer Res 42:550-555, 1982 6. Prasad KN, Cole WC, Kumar B, et al: Scientific rationale for using high-dose multiple micronutrients as an adjunct to standard and experimental cancer therapies. J Am Coll Nutr 20:450S–463S, 2001; discussion 473S–475S, 2001 7. Kumar B, Jha MN, Cole WC, et al: D-alpha tocopheryl succinate (vitamin E) enhances radiation-induced chromosomal damage levels in human cancer cells, but reduced it in normal cells. J Am Coll Nutr 21:339-343, 2002 8. Ingold KU, Burton GW, Foster DO, et al: Biokinetics of and discrimination between dietary RRR- and SRR-alpha-tocopherols in the male rat. Lipids 22:163-172, 1987 9. Prasad KN, Cole WC, Kumar B, et al: Pros and cons of antioxidant use during radiation therapy. Cancer Treat Rev 28:79-91, 2002 Journal of Clinical Oncology, Vol 24, No 6 (February 20), 2006: pp. 8e-9 DOI: 10.1200/JCO.2005.04.1327 Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.