This proposal is to investigate the mechanism of the biological effects of aromatase inhibitor, 4-hydroxandrostene-3,17-dione (4-OHA) in model systems. The goal of the research is to determine whether 4-OHA is effective for the treatment of several types of hormone-responsive cancers, based on a rationalized approach. This involves investigating whether additional activities of the compound in vivo contribute to the effectiveness of 4-OHA treatment. In breast cancer, we would determine whether 4-OHA regulates aromatase substrate production by affecting 17-hydroxylase/desmolase. We would also explore some of the normal control mechanisms of estrogen production using immunocytochemistry and in situ hybridization techniques. These studies should provide a basis for developing the most effective strategy for utilizing the compound to reduce estrogen levels. We plan to evaluate the effect of 4-OHA on the rat model for endometriosis, and the athymic mouse model bearing human endometrial cancer tissue. The mechanism of the observed effect that 4-OHA reduces progesterone receptors, concentration of receptor protein and MRNA in tissues from treated versus control animals. We would also determine whether 4-OHA has a direct effect on the growth of cultured endometrial cells. Using this system, we could determine whether the decrease in PR is due to increased degradation or decreased synthesis of the protein. We propose to investigate the effect of 4-OHA on the growth of pancreatic cancer cell lines in vitro and in athymic mice and also in carcinogen induced pancreatic tumors in hamsters. The possible role of aromatase and steroid receptors in this tumor will be investigated.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD013909-11
Application #
3312372
Study Section
Biochemical Endocrinology Study Section (BCE)
Project Start
1980-09-01
Project End
1993-03-31
Budget Start
1991-04-01
Budget End
1993-03-31
Support Year
11
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Njar, V C; Brodie, A M (1999) Comprehensive pharmacology and clinical efficacy of aromatase inhibitors. Drugs 58:233-55
Brodie, A M (1994) Aromatase inhibitors in the treatment of breast cancer. J Steroid Biochem Mol Biol 49:281-7
Koos, R D; Banks, P K; Inkster, S E et al. (1993) Detection of aromatase and keratinocyte growth factor expression in breast tumors using reverse transcription-polymerase chain reaction. J Steroid Biochem Mol Biol 45:217-25
Brodie, A M (1993) Aromatase, its inhibitors and their use in breast cancer treatment. Pharmacol Ther 60:501-15
Brodie, A (1991) Aromatase and its inhibitors--an overview. J Steroid Biochem Mol Biol 40:255-61
Banks, P K; Meyer, K; Brodie, A M (1991) Regulation of ovarian steroid biosynthesis by estrogen during proestrus in the rat. Endocrinology 129:1295-304
Inkster, S E; Brodie, A M (1991) Expression of aromatase cytochrome P-450 in premenopausal and postmenopausal human ovaries: an immunocytochemical study. J Clin Endocrinol Metab 73:717-26
Brodie, A M; Banks, P K; Inkster, S E et al. (1990) Aromatase and other inhibitors in breast and prostatic cancer. J Steroid Biochem Mol Biol 37:1043-8
Brodie, A M; Banks, P K; Inkster, S E et al. (1990) Aromatase inhibitors and hormone-dependent cancers. J Steroid Biochem Mol Biol 37:327-33
Brodie, A M; Hammond, J O; Ghosh, M et al. (1989) Effect of treatment with aromatase inhibitor 4-hydroxandrostenedione on the nonhuman primate menstrual cycle. Cancer Res 49:4780-4

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