The ways in which triarylethylene antiestrogens such as clomiphene, chlorotrianisene, nitromiphene, and tamoxifen suppress hormone dependent cell growth, including that of breast cancer cells are not fully understood. A complicating factor in developing such an understanding is an incomplete awareness of the ways in which drug metabolizing enzymes modulate antiestrogenic activity. A variety of liver microsomal metabolites resulting from oxidative biotransformation of each of the above compounds have been characterized. Most of these metabolites had estrogen receptor affinities and antiestrogenic (antiuterotropic) activities equal to or greater than those of the respective parent drugs, in the immature rat. The overall objective of this application is to determine the time course of target tissue (uterine) distribution of each of the above compounds in the immature rat, with the aims of (a) determining the amounts of previously characterized liver microsomal metabolites present; (b) isolating and characterizing any new metabolites, not found in our liver microsomal studies nor reported in other in vivo studies; (c) assessing the effects of co-substrates for drug metabolizing enzymes, which are used in combination therapy with antiestrogens, on quantitative distribution of antiestrogens and respective metabolites. Also, identification and quantitation of each drug and its metabolites in plasma and liver tissue will be carried out, since blood and liver have been shown to be important sites of distribution of triarylethylene antiestrogens. These studies will be conducted using tritium and/or carbon-14 labeled forms of the antiestrogens. Thin layer chromatography will be used extensively in metabolite isolation, determination of purity of labeled and unlabeled drugs, and in quantitative analysis of biological extracts. These studies will be carried out using Sprague-Dawley rats. Results of this work should help to define the extent to which drug metabolizing enzymes modulate the pharmacological properties of triarylethylene antiestrogens.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA028928-05
Application #
3168423
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1985-04-01
Project End
1988-03-31
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
5
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Georgia
Department
Type
Schools of Pharmacy
DUNS #
City
Athens
State
GA
Country
United States
Zip Code
30602
Ruenitz, P C; Nanavati, N T (1990) Identification and distribution in the rat of acidic metabolites of tamoxifen. Drug Metab Dispos 18:645-8
Ruenitz, P C; Thompson, C B; Srivatsan, V (1989) Characterization of MCF 7 breast cancer cell growth inhibition by the antiestrogen nitromifene (CI 628) and selected metabolites. J Steroid Biochem 33:365-9
Ruenitz, P C; Arrendale, R F; Schmidt, W F et al. (1989) Phenolic metabolites of clomiphene: [(E,Z)-2-[4-(1,2-diphenyl-2-chlorovinyl)phenoxy]ethyl]diethylamine. Preparation, electrophilicity, and effects in MCF 7 breast cancer cells. J Med Chem 32:192-7
Ruenitz, P C; Bagley, J R; Nanavati, N T (1988) Synthesis and estrogen receptor selectivity of 1,1-bis(4-hydroxyphenyl)-2-(p-halophenyl)ethylenes. J Med Chem 31:1471-5
Sutherland, R L; Watts, C K; Hall, R E et al. (1987) Mechanisms of growth inhibition by nonsteroidal antioestrogens in human breast cancer cells. J Steroid Biochem 27:891-7
Ruenitz, P C; Arrendale, R F; George, G D et al. (1987) Biotransformation of the antiestrogen clomiphene to chemically reactive metabolites in the immature female rat. Cancer Res 47:4015-9
Ruenitz, P C; Bagley, J R (1986) Metabolism of nitromiphene (CI 628) in the immature female rat: role of gastrointestinal microflora in the biotransformation of a triarylethylene antiestrogen. Cancer Res 46:6255-9
Ruenitz, P C; Bagley, J R; Watts, C K et al. (1986) Substituted-vinyl hydroxytriarylethylenes, 1-[4-[2-(diethylamino) ethoxy]phenyl]-1-(4-hydroxyphenyl)-2-phenylethylenes: synthesis and effects on MCF 7 breast cancer cell proliferation. J Med Chem 29:2511-9
Ruenitz, P C; Bagley, J R (1985) Affinity of ligands other than triarylethylenes for liver microsomal antiestrogen binding sites. Biochem Pharmacol 34:2807-9
Ruenitz, P C; Bagley, J R (1985) Comparative fates of clomiphene and tamoxifen in the immature female rat. Drug Metab Dispos 13:582-6