Inhibition of the induction of cancer by antioxidants.

Many different antioxidants have been shown to inhibit the induction of cancer by a wide variety of chemical carcinogens and/or radiation at many target sites in mice, rats, and hamsters. Evidence is accumulating that suggests that free radicals are important in all stages of chemical carcinogenesis. Both carcinogens and tumor promoters have also been shown to decrease the cellular activity of superoxide dismutase and catalase. A number of antioxidants and related compounds were tested to determine if they would inhibit either skin tumor initiation, promotion, and/or progression. In terms of skin tumor initiation, BHT, vitamin E and C and CuDIPS have been found to inhibit DMBA skin tumor initiation by approximately 50%. The mechanism of action of these compounds appears to be related to their effect on the metabolism of DMBA, since BHT and CuDIPS do not inhibit the initiating activity of BP-diol-epoxide and MNNG. Although several antioxidants do inhibit skin tumor initiation by procarcinogens, antioxidants are in general much more effective inhibitors of skin tumor promotion. BHT, BHA, parahydroxyanisole, disulfiran, and vitamin E and C inhibit skin tumor promotion by TPA and benzoyl peroxide by greater than 90%. We also determined the effect of free radical scavengers on the progression process. Of the agents tested glutathione and N-acyl dehydroalamines were the most effective in reducing carcinoma incidence. Diethyl maleate, a chemical that reduces glutathione levels, was effective in enhancing progression. In addition overexpression of g-glutamylt-ranspeptidase (GGT) which leads to a reduction in cellular glutathione levels also enhances progression. These results suggest that GGT has a functional role in skin tumor progression, and that a number of antioxidants are either effective inhibitors of skin tumor initiation, promotion, and/or progression.