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.
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.
D015127:9,10-Dimethyl-1,2-benzanthracene; D000730:Androstadienes / Q000627:therapeutic use*; D000735:Androstenedione / Q000627:therapeutic use; D000818:Animals; D047072:Aromatase Inhibitors; D004958:Estradiol / Q000097:blood; D004967:Estrogens; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D009376:Neoplasms, Hormone-Dependent / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D011919:Rats, Inbred Strains
D000730:Androstadienes; D047072:Aromatase Inhibitors; D004967:Estrogens; C052767:7-((4'-aminophenyl)thio)-1,4-androstadiene-3,17-dione; D000735:Androstenedione; D004958:Estradiol; D015127:9,10-Dimethyl-1,2-benzanthracene