Aromatase inhibition: basic concepts, and the pharmacodynamics of formestane

Aromatase inhibition is an established therapeutic option for the treatment of postmenopausal breast cancer, and current developments indicate that it will become more important over the coming years. Aromatase is a cytochrome P450 enzyme, and may be inhibited in 2 ways. First, non-steroidal inhibitors may interact directly with the prosthetic haem group of the enzyme; second, substrate analogues may compete with the normal androgen substrate for the enzyme binding site. Development of the former group has been more problematic with regard to specificity because of the widespread importance of cytochrome P450 enzymes in physiology. The pre-eminent substrate analogue is 4-hydroxyandrostenedione (formestane, Lentaron). As well as competing for the enzyme binding site, formestane is converted to a reactive intermediate which permanently inactivates the bound enzyme molecule. This mechanism is termed suicide inhibition, and has the benefit of being highly selective and of long-lasting effectiveness. In patients, formestane has been found to exert no significant effects on hormone synthetic pathways other than that of estrogen synthesis. A minor androgenic component of the drug is reflected in a dose-related fall in serum levels of sex hormone binding globulin, but this is not associated with clinical androgenic side effects. Following a series of endocrine studies a dose of 250 mg intramuscularly every 2 weeks has been selected as optimal for treatment. At this dose formestane is well tolerated and of good clinical efficacy.