Estrogen use in humans is associated with an increased risk of cancer. In rodents, estrogens induce mammary, pituitary, uterine, cervical, or kidney tumors. 2-Fluoroestradiol was previously shown in this laboratory to be estrogenic yet non-carcinogenic in the Syrian hamster renal carcinoma model. In this project, it is intended to establish the non-carcinogenic property of 2-fluoroestradiol in several other estrogen-induced tumor models and thus to generalize the concept of separation of estrogenicity from carcinogenicity by chemical modification. Specifically, lack of carcinogenic potential of 2-fluoroestradiol will be tested in 1. the estrogen and Alpha-naphthoflavone-induced liver tumor model in Syrian hamster, 2. in the estrogen-induced pituitary tumor model in Fischer 344 rats, and 3. in the estrogen/androgen-induced leiomyosarcoma of the uterine horns in Syrian hamster. In each of the three experiments, the tumor incidence will be compared with that of estradiol. Absorption from the estrogen implant and plasma estrogen levels will be measured. The estrogenic effect of the implant, pituitary LH and plasma prolactin, will be measured and compared with that of estradiol. Organ-specific DNA damage preceding carcinogenesis will be measured by a 32-P-postlabelling assay. The metabolism of 2-fluoroestradiol in rats and hamsters will be determined in vivo. In vitro, the conversion of 2-fluoroestradiol to catechol estrogens will be measured. These studies are designed to understand the mechanism of carcinogenesis by estrogens and the role of catechol estrogens in that process. Furthermore, the guiding principles for the design of a non-carcinogenic estrogen weill be developed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA043232-02
Application #
3185352
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1986-02-01
Project End
1990-01-31
Budget Start
1987-02-01
Budget End
1988-01-31
Support Year
2
Fiscal Year
1987
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
Zhu, B T; Evaristus, E N; Antoniak, S K et al. (1996) Metabolic deglucuronidation and demethylation of estrogen conjugates as a source of parent estrogens and catecholestrogen metabolites in Syrian hamster kidney, a target organ of estrogen-induced tumorigenesis. Toxicol Appl Pharmacol 136:186-93
Zhu, B T; Liehr, J G (1994) Quercetin increases the severity of estradiol-induced tumorigenesis in hamster kidney. Toxicol Appl Pharmacol 125:149-58
Zhu, B T; Roy, D; Liehr, J G (1993) The carcinogenic activity of ethinyl estrogens is determined by both their hormonal characteristics and their conversion to catechol metabolites. Endocrinology 132:577-83
Han, X L; Liehr, J G (1992) Induction of covalent DNA adducts in rodents by tamoxifen. Cancer Res 52:1360-3
Weisz, J; Bui, Q D; Roy, D et al. (1992) Elevated 4-hydroxylation of estradiol by hamster kidney microsomes: a potential pathway of metabolic activation of estrogens. Endocrinology 131:655-61
Liehr, J G; Folse, D S; Roy, D (1992) Lack of effectiveness of antiestrogens RU 39,411 or keoxifene in the prevention of estrogen-induced tumors in Syrian hamsters. Cancer Lett 64:23-9
Roy, D; Liehr, J G (1992) Target organ-specific inactivation of drug metabolizing enzymes in kidney of hamsters treated with estradiol. Mol Cell Biochem 110:31-9
Liehr, J G; Gladek, A; Macatee, T et al. (1991) DNA adduct formation in liver and kidney of male Syrian hamsters treated with estrogen and/or alpha-naphthoflavone. Carcinogenesis 12:385-9
Roy, D; Hachey, D L; Liehr, J G (1991) Determination of estradiol 2- and 4-hydroxylase activities by gas chromatography with electron-capture detection. J Chromatogr 567:309-18
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

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