Aromatase inhibition and inactivation.

Aromatase is the key enzyme in the synthesis of estrogens and mediates the conversion of androstenedione and testosterone to estrone and estradiol. Because of the importance of estrogen in stimulating breast cancers, the inhibition of estrogen synthesis is a logical approach to treatment. Aromatase is an excellent target for inhibition, because it is the last step in steroid biosynthesis, and, therefore, there are no important downstream enzymes to be affected. In addition, although aromatase is a P-450 enzyme and shares common features with other enzymes in this class, such as liver metabolizing enzymes and steroidogenic enzymes, it has unique features in the aromatizing reaction, features that are amenable to the development of selective inhibition. The approach we took to develop the first aromatase inhibitors was to design substrate analogues based on the structure of androstenedione. Some of these inhibitors, such as 4-hydroxyandrostenedione [4-OHA (later known as formestane)], also cause enzyme inactivation. Instead of being released at the end of the reaction, the substrate analogue remains bound. Therefore, the inhibitor is not required to be present at all times to maintain inhibition, and it has high enzyme specificity. Subsequently, other investigators have taken a different approach to developing compounds based on inhibitors of P-450 enzymes. High selectivity has been achieved with some of these reversible inhibitors. We have developed a unique animal model with human tumors to compare the antitumor efficacy of antiestrogens and aromatase inhibitors and to optimize their use in sequence and combination as a guide for future clinical trials.