Anti-tumor and endocrine effects of non-steroidal aromatase inhibitors on estrogen-dependent rat mammary tumors

The non-steroidal Aromatase Inhibitor CGS 20,267, at maximally effective doses in non-tumor bearing adult female rats, elicits endocrine effects mimicking those seen after surgical ovariectomy and thus induces a "medical" ovariectomy. We now report on studies characterizing the anti-tumor and endocrine effects of three orally active non-steroidal Aromatase inhibitors, CGS 20,267, CGP 45,688 and CGP 47,645, in adult female rats bearing estrogen-dependent DMBA-induced mammary tumors. Doses ranging from 3 to 3000 micrograms/kg were given by gavage once daily for 6 weeks. After 6 weeks of treatment, the ED50 for suppression of tumor volume was 10-30, 100 and 3-10 micrograms/kg for CGS 20,267, CGP 45,688 and CGP 47,645, respectively. The maximally effective dose for anti-tumor efficacy was 300, 1000 and 100 micrograms/kg for each of the three inhibitors, respectively. The observed potent anti-tumor efficacy was accompanied by potent endocrine effects. Thus, disruption of ovarian cyclicity (at maximal doses rats remained in constant diestrus) was observed in all Animals from the 2nd or 3rd week of treatment to the end of the 6-week treatment period. Uterine weight, at the maximally effective doses for each of the three inhibitors, was suppressed to between 42 and 28% of pre-treatment levels. This suppression was similar to the suppression of uterine weight (27% of pre-treatment) seen after ovariectomy. Serum estradiol concentrations in rats treated with 300 micrograms/kg CGS 20,267 were significantly suppressed to 12% of pre-treatment levels and serum luteinizing hormone (LH) concentrations were elevated 3 to 4-fold over pre-treatment levels. Thus the potent anti-tumor efficacy seen with each of the three non-steroidal Aromatase inhibitors was accompanied in each case by a variety of endocrine effects corresponding to those seen after ovariectomy.