Discussion These results suggest that high intake of vitamins C and E from supplements may reduce the risk of ovarian cancer. The data do not support the hypothesis that vitamin A and the pro-vitamin A carotenoid beta-carotene are related to ovarian cancer risk. The mechanism of action in which antioxidant vitamins C and E may elicit a protective effect has not been completely elucidated. Considerable research implicates oxygen radical scavenging, a response to oxidative stress, as the predominant role. High antioxidant consumption through supplements and diet increases cellular resistance to oxidative damage and, thus, may inhibit carcinogenesis [18-20]. Vitamins C and E have been shown to protect against cancer development in vitro and demonstrate potential in chemoprevention [21]. Vitamins C and E, along with selenium, function directly as antioxidants, decreasing the adverse effects of reactive oxygen species in vivo [22]. Carotenoids and vitamin A may influence biochemical reactions involved in oxidation, but vitamin A is not classified, according to the Institute of Medicine, as a dietary antioxidant [22]. In a clinical trial, alpha-tocopherol protected against prostate cancer [23], although two case-control studies found no difference in serum alpha-tocopherol levels between ovarian cancer cases and controls [13,14]. A recent clinical study suggested that vitamins C and/or E from supplements had no significant effect on oxidative DNA damage as measured by 8-hydroxydeoxyguanosine in nonsmoking adults, although prior antioxidant supplement use was associated with lower urinary 8-hydroxydeoxyguanosine [24]. Smoking did not significantly modify the effects of anti-oxidants. However, the protective effect of vitamin C differed between smokers and nonsmokers to some extent. Women who never smoked received slightly more benefit from high intake of vitamin C from supplements than did those who smoke currently or smoked in the past. One possible explanation for this difference is that in smokers an increased utilization of ascorbic acid and alpha-tocopherol, in response to higher oxidative stress, contributes to the reported lower plasma antioxidant concentrations [25]. Studies have shown that smokers have lower circulating levels of antioxidant micronutrients and carotenoids than do nonsmokers [26]. Smokers require even greater quantities of antioxidants than do nonsmokers and may receive less protection from equal intakes. We were not able to examine effect modification by current or past smoking because of the limited number of current smokers. Rock et al. [27] found that women who maximize their antioxidant intake from food sources are more likely to use ancillary antioxidant supplements than women who consume foods lower in antioxidant nutrition. In a study of breast cancer, women with diets high in vitamin and mineral content were more likely to use nutritional supplements than were women with lower intake of antioxidant-rich foods [27]. Our results showed a modest, but nonsignificant, association between supplement use and higher antioxidant intake from diet. This suggests that supplement users tend to consume higher quantities of antioxidants from foods than do non-supplement users. However, dietary consumption of antioxidants was not related to supplement use in The Netherlands cohort study [28]. No previous studies have reported on the associations between supplements and ovarian cancer risk. In five studies that measured vitamin A from diet, the ORs associated with the highest categories ranged from 0.7 [12] to 1.1 [6]. Our results for the intake of vitamin A from foods were similar to those reported in earlier studies. In two studies that measured vitamin C from diet, the ORs associated with the highest categories of use of vitamin C were 0.7 [12] to 1.0 [6]. Our findings on vitamin E were less consistent with the one other study that reported on dietary vitamin E [6], which found ORs of 0.7 and 0.91 for levels of intake similar to that for which we found an OR of 1.7. Our results for beta-carotene from food, showing no association, were similar to those reported by Kushi et al. [6] and La Vecchia et al. [9] but differed from the protective effect found by Engle et al. [7], Slattery et al. [12], and Risch et al. [15]. All analyses were controlled for potential sources of confounding. Residual confounding may have influenced the results. On average, community controls were younger than cases. The results were adjusted for age, and age was not associated with supplement use in this population. Selection bias due to low participation in the control groups may have led to an overestimation of the true effect if participating controls tended to be healthier than the population from which they were selected. However, there were no significant differences in the proportion of users of individual supplements between cases and controls; only the dose levels were greater in the control groups. Differences between the two control groups were apparent. The hospital-based convenience controls tended to be more similar to the cases than to the community control group. As a result, analyses with total controls were attenuated toward the null compared with analyses using only the community control group. Description and interpretation of these control groups have been explained in detail by Olson et al. [17]. The community control group is more likely than the convenience control group and other studies to be representative of the target population, which gave rise to the cases. As a result, we focus our results on the community control analyses. However, the effect of vitamins C and E from supplements also suggests a reduced risk of ovarian cancer in analysis that included the convenience controls as well. In conclusion, vitamin C and E supplements, from multi-vitamins and from individual vitamin C and E tablets, are associated with a reduced risk of ovarian cancer. In this study, supplemental vitamin C > 90 mg/day and vitamin E > 30 mg/ day are associated with a reduced risk of epithelial ovarian cancer. Other research also points to the need for relatively high levels of these vitamins for a protective effect, and if a protective effect does exist for vitamins C and E, optimal levels of intake might not be achievable from diet alone [29]. If a threshold level of protection does exist for certain anti-oxidants, use of supplements provides the necessary consumption levels to elicit a protective effect [29]. Gey [30] reported that threshold serum levels of 40-50 µmol/l for vitamin C and 28-30 µmol/l for vitamin E might exist to elicit a protective effect against chronic disease. Carr and Frei [31] reviewed substantial clinical and epidemiological data and suggested that an intake of 90-100 mg/day of vitamin C is required for optimum reduction of chronic disease. They [31] proposed increasing the US Recommended Dietary Allowance (RDA) values. Our results support an increase in RDA levels for vitamins C and E, where minimum protective doses are each 1.5 times the US RDA values [60 mg/day of vitamin C and 30 IU/day (20.1 mg) of vitamin E]. Acknowledgements Address correspondence to A. T. Fleischauer, Dept. of Epidemiology, CB 7435, School of Public Health, University of North Carolina, Chapel Hill, NC 27599. Nutr Cancer 40(2):92-98, 2002. © 2002 Lawrence Erlbaum Associates, Inc Remember we are NOT Doctors and have NO medical training. 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