Aromatase inhibition by an enzyme-activated irreversible inhibitor in human carcinoma cell cultures.

7 alpha-(4'-Amino)phenylthio-1,4-androstadiene-3,17-dione (7 alpha-APTADD), a potent enzyme-activated irreversible inhibitor, was examined in two different human cell culture lines, MCF-7 human mammary carcinoma cells and JAr choriocarcinoma cells. Both the MCF-7 and JAr cell culture systems exhibit aromatase activity, and 7 alpha-APTADD was evaluated for its aromatase-inhibitory activity, for its ability to inactivate the enzyme complex, and for the time course of recovery of enzymatic activity. This inhibitor produced a dose-dependent inhibition of aromatase activity in MCF-7 cells and in JAr cells, with EC50 values of 91 and 7.3 nM, respectively. Two other steroidal inhibitors, 7 alpha-(4'-amino)phenylthio-4-androstene-3,17-dione and 4-hydroxyandrostenedione, produced similar dose-response curves and EC50 values, while the nonsteroidal aminoglutethimide was less effective. Both cell culture systems exhibited prolonged inhibition of aromatase activity following exposure to 7 alpha-APTADD, suggesting enzyme inactivation by this inhibitor. Thus, 7 alpha-APTADD is an effective inhibitor of aromatase in MCF-7 mammary carcinoma cells and in JAr choriocarcinoma cells. These studies encourage further development of this group of medicinal agents for the treatment of estrogen-dependent mammary carcinoma.