S Dauvois, CS Geng, C Levesque, Y Merand and F Labrie
Medical Research Council Group in Molecular Endocrinology, CHUL Research Center, Quebec, Canada.
The effects of the androgen dihydrotestosterone (DHT) and of the androgenic steroid medroxyprogesterone acetate were studied on the growth of human ZR-75-1 breast carcinoma in athymic mice. The possibility of additive inhibitory effects of DHT and the new steroidal antiestrogen N-n-butyl, N-methyl-11-[16' alpha- chloro-3',17' alpha-dihydroxyestra-1',3',5'(10')trien-7' alpha-yl]undecanamide (EM-170) was also investigated on tumor growth. Removal of the high dose 17 beta-estradiol (E2) implants used to optimally stimulate initial ZR-75-1 tumor development in ovariectomized mice led to a progressive decrease in tumor area to 50.2 +/- 8% (SEM) of original tumor size 40 days after E2 deprivation. Additional treatment with the androgen DHT led to a more rapid fall in tumor volume, which already reached 57% of pretreatment values at 11 days. Whereas physiological implants of E2 led to a progressive increase in tumor size to about 180% above original size after 40 days, physiological plasma levels (205 +/- 37.2 pg/ml or approximately 0.67 nM) of DHT completely reversed the stimulatory effect of E2. Similar inhibitory effects on E2-stimulated tumor growth were achieved with the synthetic androgenic steroid medroxyprogesterone acetate. When the steroidal antiestrogen EM-170 at the dose of 30 micrograms/day was used simultaneously with DHT, tumor area was further reduced from 99.0 +/- 9.5% (DHT alone) to 58.8 +/- 18% when both DHT and EM-170 were administered together for 40 days compared with 169 +/- 22.2% in control E2-stimulated animals. The present data show that the androgen DHT as well as medroxy-progesterone acetate are potent inhibitors of E2-stimulated human ZR-75-1 breast cancer cell growth in vivo. Moreover, the inhibitory effect of DHT can be further increased by addition of the antiestrogen EM-170, thus suggesting the interest of combiningthese 2 classes of compounds acting, at least partially, through different mechanisms, in order to improve breast cancer therapy in women.