Estrogens are involved in numerous physiological processes including the development and maintenance of the female sexual organs, the reproductive cycle, reproduction, and various neuroendocrine functions. These hormones also have crucial roles in certain disease states, particularly in mammary and endometrial carcinomas. Inhibitors of estrogen biosynthesis have potential use as pharmacological tools and therapeutic agents in the treatment of various estrogen-dependent disease states, such as advanced breast cancer. Aromatase inhibitors would effectively lower estrogen levels in all tissues where produced (such as adipose tissue in post-menopausal women) and result in tumor regression. Several aromatase inhibitors are being examined in clinical trials and produced positive results in women with hormone-dependent breast cancer. Newer aromatase inhibitors with higher potency, greater selectivity, and fewer side effects are needed. Several 7alpha-substituted steroidal aromatase inhibitors have been developed by our laboratory and have the highest affinities for aromatase and greatest inhibitory activities in vitro of all known aromatase inhibitors. Knowledge of in vivo pharmacology, pharmacokinetics, and metabolism of these effective inhibitors are critical for further development. the objective of this collaborative, multi-disciplinary research is to perform preclinical pharmacology investigations of new steroidal aromatase inhibitors being developed for the treatment of advanced estrogen-dependent breast cancer. New competitive aromatase inhibitors (7alpha-substituted 4-androstene-3, 17- diones) and enzyme-activated inhibitors (7alpha-substituted 1,4- androstadiene-3,17-diones) have been prepared in our laboratories. Further studies of these new analogs in cell culture systems and in vivo are essential in the development of these inhibitors as effective therapeutical agents for the treatment of estrogen-dependent cancers.
The specific aims are (1) to examine effects of aromatase inhibitors on cell growth and steroid biochemistry in cancer cell cultures, (2) to investigate inhibition of other steroidogenic enzymes by 7alpha- substituted steroidal aromatase inhibitors, (3) to assess in vivo antitumor activity, to examine the pharmacology, and to determine pharmacokinetics of these agents, and (4) to perform acute toxicity testing of selected inhibitors in rats. These studies will provide important information on the potential of the compounds as medicinal agents in the treatment of breast cancer and will provide the data needed to submit an IND application for the first clinical evaluation of a 7alpha-substituted steroidal agent for the treatment of patients with advanced estrogen-dependent breast cancer.
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