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Cancer Res. 1988 Dec 1;48(23):6808-10.

Effects of the aromatase inhibitor 7 alpha-(4'-amino)phenylthio-4-androstene-3,17-dione on 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in rats.

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College of Pharmacy, Ohio State University, Columbus 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 alpha-Substitution of androstenedione results in inhibitors of enhanced affinity for aromatase, with 7 alpha-(4'-amino)phenylthio-4-androstene-3,17-dione (7 alpha-APTA) exhibiting an apparent Ki of 18 nM and being among the most potent competitive inhibitors produced. The effects of this potent competitive 7 alpha-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 alpha-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 alpha-APTA at 50 mg/kg/day and estradiol at 0.3 microgram/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 alpha-APTA at the end of the treatments. Thus, 7 alpha-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.

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