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.
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