Co-administration of vitamin C to estrogen-treated Syrian hamsters significantly lowered the incidence of estradiol-induced renal tumors.
The aim of the proposed study is the elucidation of the mechanism of action of vitamin C in this tumor model. The knowledge of the mechanism of tumor prevention by C will aid in understanding the mechanism of tumorigenesis by steroidal estrogens. Moreover, the general tumor preventing value of vitamin C will be defined by these studies. The working hypothesis is that vitamin C prevents tumors by reduction of reactive quinone intermediates formed by oxidation of steroidal catechol estrogen metabolites. In preliminary experiments with the stilbene estrogen DES, we demonstrated that DES quinone is the reactive genotoxic intermediate of DES in vivo and that this quinone is reduced by vitamin C to DES in vitro and in vivo. Analogous experiments with estradiol and ethinylestradiol are proposed here. Estradiol will be investigated because it is the natural hormone and ethinylestradiol because it is a main component of many estrogenic medications. Specifically, I will: 1. Establish in vitro DNA adduct patterns of quinones formed from catechol estrogens of estradiol and ethinylestradiol. 2. Inject the catechol estrogens into hamsters. Compare DNA adduct patterns in vivo with those obtained in vitro. Demonstrate decreased adduct intensities in vitro and in vivo by administration of vitamin C. 3. Inject estradiol or ethinylestradiol into hamsters and compare DNA adduct patterns with those obtained in vitro using quinones. Correlate adduct concentrations and tumor incidence in hamsters (with and without additional exposure to vitamin C). 4. Elucidate structures by spectroscopic methods of the biologically relevant adducts formed in vitro and in vivo. 5. Measure concentrations of catechol estrogen quinone metabolites in hamsters. Correlate metabolite and DNA adduct concentrations with tumor incidence (with or without additional exposure to vitamin C). 6. Analyze DNA of human tissue (placenta, mammary, uterus) for the possible occurrence of catechol estrogen quinone DNA adducts. Compare adduct profiles with those obtained in vitro and identify adduct structures. Attempt to correlate adduct intensities with disease states of patients.
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