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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA044069-06
Application #
3186616
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1986-09-01
Project End
1992-08-31
Budget Start
1991-09-01
Budget End
1992-08-31
Support Year
6
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555
Liehr, J G (1991) Vitamin C reduces the incidence and severity of renal tumors induced by estradiol or diethylstilbestrol. Am J Clin Nutr 54:1256S-1260S
Gladek, A; Liehr, J G (1991) Transplacental genotoxicity of diethylstilbestrol. Carcinogenesis 12:773-6
Roy, D; Weisz, J; Liehr, J G (1990) The O-methylation of 4-hydroxyestradiol is inhibited by 2-hydroxyestradiol: implications for estrogen-induced carcinogenesis. Carcinogenesis 11:459-62
Liehr, J G; Roy, D; Ari-Ulubelen, A et al. (1990) Effect of chronic estrogen treatment of Syrian hamsters on microsomal enzymes mediating formation of catecholestrogens and their redox cycling: implications for carcinogenesis. J Steroid Biochem 35:555-60
Liehr, J G; Roy, D (1990) Free radical generation by redox cycling of estrogens. Free Radic Biol Med 8:415-23
Liehr, J G (1990) Genotoxic effects of estrogens. Mutat Res 238:269-76
Roy, D; Liehr, J G (1989) Changes in activities of free radical detoxifying enzymes in kidneys of male Syrian hamsters treated with estradiol. Cancer Res 49:1475-80
Liehr, J G; Roy, D; Gladek, A (1989) Mechanism of inhibition of estrogen-induced renal carcinogenesis in male Syrian hamsters by vitamin C. Carcinogenesis 10:1983-8
Roy, D; Bui, Q D; Weisz, J et al. (1989) Comparison of assays for catechol estrogen synthase activity: product isolation vs radioenzymatic catechol-O-methyltransferase-coupled procedures. J Steroid Biochem 33:243-9
Roy, D; Liehr, J G (1989) Metabolic oxidation of diethylstilbestrol to diethylstilbestrol-4',4""-quinone in Syrian hamsters. Carcinogenesis 10:1241-5

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