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Effects of the Aromatase Inhibitor 7-(4'-Amino)phenylthio-4-androstene-3,17-dione on 7,12-Dimethylbenz(a)anthracene-induced Mammary Carcinoma in Rats¹

The College of Pharmacy and The OSU Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210

Inhibitors of aromatase, the cytochrome P-450 enzyme complex responsible for the biosynthesis of estrogens, may be useful therapeutic agents for the treatment of estrogen-dependent disease states such as breast and endometrial cancer. 7-Substitution of androstenedione results in inhibitors of enhanced affinity for aromatase, with 7-(4'-amino)phenylthio-4-androstene-3,17-dione (7-APTA) exhibiting an apparent K_i of 18 nM and being among the most potent competitive inhibitors produced. The effects of this potent competitive 7-substituted C₁₉ aromatase inhibitor on reduction of the number and size of the 7,12-dimethylbenz(a)anthracene-induced mammary tumors in rats was investigated. Tumor-bearing rats receiving 25 or 50 mg 7-APTA/kg/day demonstrated reductions in tumor volumes during the first week. Tumor volumes continued to decrease during the studies, resulting in tumor volume reductions of approximately 40 and 80%, respectively. Tumors in rats of the control group receiving only vehicle steadily increased in size during the studies. The tumor reductions in a 50-mg/kg/day-treated group were reversed by coadministration of 7-APTA at 50 mg/kg/day and estradiol at 0.3 µg/kg/day for the last 3 weeks, indicating that the tumors were still responsive to estrogen. Plasma levels of estradiol were lower in the animals treated with 7-APTA at the end of the treatments. Thus, 7-APTA is effective in reducing tumor volumes in the estrogen-dependent 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma rat model. These results encourage further development of these steroids as potential medicinal agents for the treatment of estrogen-dependent disease states such as breast and endometrial cancer.

¹ This work was supported by NIH Grant P30-CA16058, American Cancer Society Grant BC-482, and a United Cancer Council Grant.

² To whom requests for reprints should be addressed, at College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210.

Received 4/29/88. Revised 8/25/88. Accepted 9/ 1/88.

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