Prevention of development of dimethylbenz(a)anthracene (DMBA)-induced mammary tumors in the rat by the new nonsteroidal antiestrogen EM-800 (SCH57050).

The effect of EM-800, a new non-steroidal antiestrogen having pure antiestrogenic activity, was studied on chemical carcinogenesis induced by dimethylbenz(a)anthracene (DMBA) as well as on serum lipids and bone mass in the rat. Treatment with EM-800 orally, once daily, for 282 days (9 months), starting 3 days before DMBA administration, decreased the incidence of tumors from 95% in control animals to 60% (p < 0.01), 38% (p < 0.01), and 28% (p < 0.01) at the daily doses of 25 microg, 75 microg, and 250 microg, respectively. The average number of tumors per animal decreased from 4.5 +/- 0.5 tumors in the control group to 0.9 +/- 0.2 (p < 0.01), 0.5 +/-0.2 (p < 0.01), and 0.3 +/- 0.1 (p < 0.01) tumors in the rats treated with the above-indicated doses of the anti-estrogen. In addition, treatment with the increasing doses of EM-800 reduced serum cholesterol levels to 64%, 56%, and 48% of control, while serum triglycerides decreased to 31%, 28%, and 30% of control. Bone mineral content (BMC) and bone mineral density (BMD) of total skeleton, femur, and lumbar spine were not significantly affected following 282 days of treatment with EM-800. However, treatment with EM-800 inhibited the urinary ratio of hydroxyproline to creatinine (HP/Cr) from 14.0 +/- 3.90 micromol/mmol in controls to 7.6 +/-0.8 (p < 0.05), 6.8 +/- 0.8 (p < 0.01), and 6.8 +/- 1.1 (p < 0.01) micromol/mmol, respectively, while the same treatment had no effect on serum total alkaline phosphatase (tALP) activity or urinary calcium and phosphorus excretion. The 25 microg, 75 microg, and 250 microg daily doses of EM-800 inhibited uterine weight by 35% (p < 0.01), 62% (p < 0.01), and 66% (p < 0.01), while vaginal weight was reduced by 8% (p < 0.05), 30% (p < 0.01), and 38% (p < 0.01), respectively. In agreement with the 27% increment (p < 0.05) in ovarian weight at the highest anti-estrogen dose used, serum androstenedione (p < 0.05), androst-5-ene-3beta,17beta-diol (p < 0.01), testosterone (p < 0.05), and estradiol (p < 0.01) levels were increased. The present data show that EM-800 prevents the development of DMBA-induced mammary tumors while simultaneously inhibiting uterine and vaginal weight, reducing serum cholesterol and triglyceride levels, and having no adverse effect on bone mass following 9 months of treatment in the rat.