Inhibition of aromatase with CGS 16949A in postmenopausal women.

Potent, specific, and nontoxic inhibitors of aromatase would be useful for experimental studies and for use in the treatment of breast cancer and other disorders. We evaluated the effects of CGS 16949A, a nonsteroidal inhibitor of aromatase activity, in 12 postmenopausal women with breast cancer by measuring plasma and/or urinary androgens and estrogens after oral administration of CGS 16949A at doses ranging from 0.6-16 mg daily; each dose was given for 2 weeks. The 0.6-mg daily dose partially lowered estrogen levels, and maximum reduction occurred at doses of 2-16 mg daily. The fall in plasma and urinary estrogens without a concomitant fall in plasma androgens confirmed the blockade of aromatase activity. The degree of estrogen reduction was greatest for urinary estrone [to 27 +/- 3% (+/- SE) of basal], followed in order by plasma estrone sulfate (30 +/- 4%), plasma estrone (32 +/- 6%), urine estradiol (45 +/- 5%), and plasma estradiol (65 +/- 5%). Use of gas liquid chromatography-mass spectrometry techniques revealed similar patterns of reduction in catechol estrogens, estriol, and total urinary estrogens, suggesting that CGS 16949A does not alter the pathways of estrogen metabolism. The degree of estrogen reduction was remarkably similar to that caused with aminoglutethimide. At doses of 4-16 mg daily, CGS 16949A inhibited the C21-hydroxylase enzyme as well, based on concomitant rises in plasma androstenedione, testosterone, and 17 alpha-hydroxyprogesterone. This effect was insufficient to lower urinary cortisol excretion during the study. However, a statistically significant blunting of plasma cortisol responses to ACTH occurred with the 16-mg daily dose. No changes in plasma dehydroepiandrosterone sulfate levels or in thyroid, hematological, liver, or renal parameters were found. No significant side-effects of the medication were encountered. CGS 16949A appears to be a specific inhibitor of aromatase at doses below 4 mg daily and to lack apparent side-effects or toxic actions at doses up to 16 mg daily. This agent shows promise as a potent aromatase inhibitor for physiological and clinical studies.