1. Estrogen antagonists. Aromatase inhibitors, their pharmacology and application

Aromatase inhibitors, 4-OHA, 4-acetoxy-A and ATD cause competitive inhibition and inactivation of aromatase in vitro. The latter property may account for sustained aromatase inhibition observed in vivo, even though 4-OHA is cleared rapidly from the circulation. Thus, all 3 compounds inhibit the prosestrus oestrogen surge in rats. Treatment with 4-OHA for one oestrus cycle is sufficient to block ovulation for at least 10 additional days. Although ovarian oestrogen production was reduced by long-term inhibitor treatment, gonadotrophins remained at basal levels, suggesting a direct effect of 4-OHA on gonadotrophins. Marked regression of DMBA-induced mammary tumours occurred in rats treated with aromatase inhibitors. The compounds were more effective alone against these tumours than when combined with the antioestrogen, tamoxifen. Sustained antitumour effects of 4-OHA were observed in rats treated twice daily (50 mg/kg/day) for 9 days and twice weekly thereafter for 20 weeks. Tumours regressed during the first 9 days and 18/19 tumours remained suppressed for 20 weeks. The results in animal models suggest that highly potent aromatase inhibitors may be useful for breast cancer treatment and for other oestrogen related clinical problems.