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 mu g, 75 mu g, and 250 mu g, 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 antiestrogen. 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 mu mol/mmol in controls to 7.6 +/- 0.8 (p < 0.05), 6.8 +/- 0.8 (p < 0.01), and 6.8 1 1.1 (p < 0.01) mu mol/mmol, respectively, while the same treatment had no effect on serum total alkaline phosphatase (tALP) activity or urinary calcium and phosphorus excretion. The 25 mu g, 75 mu g, and 250 mu g 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 antiestrogen dose used, serum androstenedione (p < 0.05), androst-5-ene-3 beta,17 beta-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.