The antitumor effect of the new non-steroidal
aromatase inhibitor fadrozole (4-(5,6,7,8-tetrahydroimidazo[1,5-a] pyridin-5-yl)
benzonitrile monohydrochloride,
CGS 16949A, CAS 102676-31-3) was studied in female Sprague-Dawley rats with
7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary
tumors.
CGS 16949A was administered p.o. at 3 different schedules of once daily (0.5, 2 mg/kg), once every 3 days (1.5, 6 mg/kg) and once every 7 days (3.5, 14 mg/kg) treatments. A daily treatment of 0.5 mg/kg
CGS 16949A was more effective than the once every 7 days treatment of 14 mg/kg on the
tumor growth. The most significant reductions of the
tumor diameter,
tumor number, plasma
sex hormone levels were observed in once daily treatment group of 2 mg/kg
CGS 16949A. The antiproliferative effect of
CGS 16949A on the post-menopausal model of DMBA-induced rat mammary
tumor was studied. A post-menopausal model was induced by the combination of
ovariectomy and
androstenedione continuously released from an osmotic pump placed subcutaneously.
Androstenedione inhibited the
ovariectomy-induced
tumor volume reduction. Twice daily treatment of 0.25 mg/kg
CGS 16949A counteracted the
androstenedione-induced
tumor volume retention. These data suggest that continuous treatment of a low dose is more effective than intermittent treatment of a high dose and
aromatase enzymes of tissues other than ovaries may participate in the production of
estradiol in postmenopausal model of DMBA-induced rat mammary
tumors.