Development of steroidal and nonsteroidal inhibitors of aromatase for the treatment of hormone-dependent breast cancer

Aromatase (estrogen synthase) is an enzyme complex responsible for the conversion of androgens to estrogens in the final step in steroidogenesis. Estrogens play important roles in both normal physiology and reproduction and in certain estrogen-responsive disease states, such as hormone-dependent breast cancer. Approximately two-thirds of newly diagnosed breast cancer cases are hormone-dependent breast cancer, and estrogens have potent mitogenic effects on this type of breast cancer. Decreasing circulating estrogen levels could result in effective therapy for hormone-dependent breast cancer. Since aromatase is the rate limiting step for the biosynthesis of estrogens, it is an appropriate target for inhibition. Over the past two decades, both steroidal and nonsteroidal aromatase inhibitors have been developed that are very potent compounds and very selective for aromatase versus other steroidogenic cytochrome P450 enzymes. The steroidal inhibitor 4-hydroxyandrostenedione has demonstrated clinical efficacy in the treatment of hormone-dependent breast cancer in postmenopausal women and is currently available in Europe. Several potent and selective nonsteroidal aromatase inhibitors are now undergoing extensive Phase II and Phase III clinical trials and should become available within the next few years for the treatment of breast cancer in postmenopausal women.