Rationale for using high-dose multiple dietary antioxidants as an adjunct to radiation therapy and chemotherapy.

Most oncologists do not recommend antioxidants to their patients during standard therapy, but some may recommend them at low doses after completion of therapy. However, about 60% of patients take antioxidants during standard therapy without the knowledge of their oncologists. Therefore, a rational strategy for the use of antioxidants and their derivatives in combination with standard therapy may be harmful, because endogenously made antioxidants (glutathioneand antioxidant enzyme–elevating agents) at any dose—or dietary antioxidants and their derivatives, such as vitamin A, including retinoic acid; vitamin C; vitamin E as d-tocopheryl succinate ( -TS); and natural -carotene at low doses—may protect cancer cells during therapy, and because low doses of individual dietary antioxidants may stimulate the proliferation of residual cancer cells. Appropriate therapy should be developed. Dietary antioxidants at high doses induce differentiation, proliferation inhibition, and apoptosis, depending on the dose and type of antioxidants, treatment schedule, and type of tumor cells, without producing similar effects on most normal cells in vitro and in vivo (1–2). The growth-inhibiting effect of these agents on cancer cells may not involve antioxidant action but may involve changes in expression of genes and levels of proteins and translocation of certain proteins from one cellular compartment to another. A mixture of retinoic acid, -TS, vitamin C, and carotenoids produces 50% proliferation inhibition in human melanoma cells in culture at doses that do not reduce proliferation when used individually. Doubling only the dose of vitamin C in the mixture causes about 90% proliferation inhibition. In addition to dietary antioxidants and their derivatives, endogenously made antioxidants such as overexpression of mitochondrial manganesesuperoxide dismutase (Mn-SOD) and the glutathione-elevating agent N-acetylcysteine (NAC) reduce the proliferation of cancer cells in culture. Laboratory data (1–2) show that antioxidants protect cancer cells when dietary or endogenously made antioxidants are administered only one time, at low doses that do not affect the proliferation of cancer cells, shortly before therapeutic agents. For example, a single low dose of -TS, d-tocopherol ( -T), vitamin C, or NAC administered shortly before irradiation reduces the effectiveness of x-irradiation in in vitro and in vivo models. Overexpression of Mn-SOD enhances the radioresistance of tumor cells in culture. Laboratory experiments (1–2) also show that growth-inhibiting doses of -TS, vitamin C, and retinoic acid administered before and after irradiation enhance the effect of x-irradiation on cancer cells in culture and protect normal fibroblasts against some radiation damage. Vitamin A and -carotene at high doses, administered daily before x-irradiation and during the entire observation period, produces a 90% cure rate in mice with transplanted breast adenocarcinoma; whereas treatment with radiation alone or antioxidant alone is ineffective. The administration of multiple dietary antioxidants (vitamins A, C, and E) reduces myelosuppression without protecting cancer cells in mice treated with radioimmunotherapy. Several studies report that growth-inhibiting concentrations of vitamin C, -TS, vitamin A (including retinoids), and carotenoids including -carotene enhance the effect of chemotherapeutic agents on mouse and human cancer cells in culture. The extent of this enhancement depends on dose and form of the antioxidants; treatment schedule, dose and type of chemotherapeutic agents; and type of tumor cell. A mixture of retinoic acid, -TS, vitamin C, and carotenoids at growthinhibiting concentrations enhances the effect of some chemotherapeutic agents on human melanoma cells in culture. Vi1 Presented as part of the conference “Free Radicals: The Pros and Cons of Antioxidants,” held June 26–27 in Bethesda, MD. This conference was sponsored by the Division of Cancer Prevention (DCP) and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Department of Health and Human Services (DHHS); the National Center for Complementary and Alternative Medicine (NCCAM), NIH, DHHS; the Office of Dietary Supplements (ODS), NIH, DHHS; the American Society for Nutritional Science; and the American Institute for Cancer Research and supported by the DCP, NCCAM, and ODS. Guest editors for the supplement publication were Harold E. Seifried, National Cancer Institute, NIH; Barbara Sorkin, NCCAM, NIH; and Rebecca Costello, ODS, NIH. 2 Supported by the Shafroth Memorial Fund. 3 To whom correspondence should be addressed. E-mail: [email protected]. 4 Abbreviations used: -T, d-tocopherol; -TS, d-tocopheryl succinate; 5-FU, 5-fluorouracil; Mn-SOD, mitochondrial manganese-superoxide dismutase; NAC, N-acetylcysteine.