INHIBITORY EFFECT OF A STEROIDAL ANTIESTROGEN (EM-170) ON ESTRONE-STIMULATED GROWTH OF 7,12-DIMETHYLBENZ(A)ANTHRACENE (DMBA)-INDUCED MAMMARY-CARCINOMA IN THE RAT

Recently, compounds having pure antiestrogenic activity have become available. In this study, we examined the activity of the new steroidal antiestrogen EM-170 (N-n-butyl, N-methyl-11-(16'alpha-chloro-3',17'alpha-dihydroxy-estra-1',3',5' (10')-trien-7'alpha-yl) undecanamide) on the growth of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma stimulated by treatment with estrone (E(1)), a steroid known to play an important role as precursor of 17 beta-estradiol (E(2)), especially in postmenopausal women. Twenty-five days after ovariectomy (OVX), tumor volume in control OVX animals decreased to 51.4 +/- 11% of the initial volume; treatment with E(1), administered by Silastic implants, stimulated tumor growth to 179 +/- 21%. Treatment with the antiestrogen EM-170 at a dose of 200 mu g (twice daily) not only completely reversed the stimulatory effect of E(1), but also inhibited tumor growth to 30.5 +/- 9.6%, an effect that is 41% (P < 0.01 vs OVX control) greater than that of ovariectomy alone. At a relatively low dose of 40 mu g (twice daily), 20 days of treatment with EM-170 reversed by 55% the stimulatory effect of E(1) (1.0 mu g, subcutaneously twice daily) on tumor growth in OVX animals. On the other hand, the antiestrogen also induced a significant inhibitory effect on 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) activity in the DMBA-induced mammary tumors, an effect that is in agreement with the marked reduction caused by the same treatment on tumor estradiol (E(2)) levels in E(1)-treated OVX animals. The present data show that the new steroidal antiestrogen EM-170 exerts a potent inhibitory effect in vivo on E(1)-stimulated growth of DMBA-induced mammary tumors, an effect that is probably mediated by both its antiestrogenic activity at the receptor level and its inhibitory effect on 17 beta-HSD, thus inhibiting local E(2) formation and facilitating the action of the antiestrogen at the receptor level.