Clinical use of aromatase inhibitors in human breast carcinoma

The biological importance of aromatase rests in the concept that this is the rate-limiting enzyme involved in estrogen biosynthesis. Approx. one-third of human breast carcinomas depend upon estrogen for growth. Blockade of estrogen biosynthesis, then, provides an effective means of causing tumor regression in selected patients. The side effects and lack of specificity of the aromatase inhibitor, aminoglutethimide, provided the impetus toward development of nonsteroidal inhibitors of aromatase. Several compounds are currently being evaluated. Pyridoglutethimide is a derivative of aminoglutethimide which does not inhibit cholesterol side-chain cleavage and possesses no CNS sedative properties; the Ki for aromatase is 1100 nM, somewhat higher than for aminoglutethimide, 600 nM. CGS 16949A is a highly potent inhibitor of aromatase which is an imidazole derivative. This compound inhibits aromatase with a Ki of 0.19 nM whereas inhibition of C11-hydroxylase activity occurs at 10(-6) M. In clinical trials, this compound lowers plasma estrogen levels, blocks peripheral aromatization as documented by isotopic kinetic studies, and causes tumor regression. Phase III trials with this drug are now ongoing. Another agent, R76713, represents another highly potent and specific aromatase inhibitor with little toxicity in animal studies. The Ki for placental aromatase is 0.8 nM and this compound is approx. 500-fold more potent than aminoglutethimide. Phase I clinical studies in patients reveal a marked reduction in estrogen production. These compounds represent the most promising of a wide variety of agents currently being tested for their aromatase inhibitory properties.