Comparative studies of aromatase inhibitors in relation to the significance of estrogen synthesis in human mammary tumors.

The inhibitory activity of aminoglutethimide, 4-hydroxyandrostenedione, 7 alpha-(4'-amino)phenylthioandrostenedione, and cyanoketone (2 alpha-cyano-4,4,17 alpha-trimethyl-17 beta-hydroxy-5-androstene-3-one) on androgen aromatization by human mammary tumors was examined. Androstenedione and dehydroepiandrosterone were incubated with mammary tumor homogenates in the presence of a reduced nicotinamide adenine dinucleotide phosphate-generating system with or without inhibitor. All four compounds were found to be equally effective in inhibiting estrogen synthesis from dehydroepiandrosterone, but only aminoglutethimide, 4-hydroxyandrostenedione, and 7 alpha-(4'-amino)phenylthioandrostenedione were capable of inhibiting androstenedione aromatization. Inhibitions of androgen aromatization ranging between 81 and 97% were found and were essentially similar for both estrogen receptor-negative and estrogen receptor-positive tumors. Kinetic analysis showed 7 alpha-(4'-amino)phenylthioandrostenedione to be the most effective inhibitor with apparent Ki of 0.034 microM, followed by aminoglutethimide (Ki 0.26 microM) and 4-hy droxyandrostenedione (Ki 01.47 microM) using androstenedione as a substrate. These results are discussed in relation to the significance of estrogen synthesis in mammary tumors.