Comparison of the effects of the new orally active antiestrogen EM-800 with ICI 182 780 and toremifene on estrogen-sensitive parameters in the ovariectomized mouse.

The nonsteroidal antiestrogen EM-800 is approximately 10-fold more potent than ICI 182 780, the most potent known steroidal antiestrogen, at inhibiting estrone-stimulated uterine weight in ovariectomized mice (half-maximal inhibitory daily s.c. doses of 0.2 and 2.0 microg, respectively). At maximal doses, however, both compounds lead to a similar maximal 90% inhibition of estrone-stimulated uterine weight. A 10-fold higher activity of EM-800 compared with ICI 182 780 was also observed on estrone-stimulated vaginal weight, with maximal inhibitions of 96% and 90%, respectively, achieved by the two compounds. In addition, EM-800 injected s.c. or administered orally led to a marked loss of uterine and vaginal estrogen receptor levels measured by binding assay, whereas ICI 182 780 exerted no inhibitory effect on this parameter under the experimental conditions used. Comparable effects were observed when estrogen receptor protein levels were measured by enzyme immunoassay. After oral administration, EM-800 exerted maximal 83% and 88% inhibitions of uterine and vaginal weight, respectively, whereas maximal inhibitions limited to 51% and 67% were achieved with toremifene. This limited inhibition by toremifene of the stimulatory effect of estrone on uterine and vaginal weight is probably due to the intrinsic estrogenic activity of the compound. The present data also show that the steroidal antiestrogen ICI 182 780 has less than 3% the activity of EM-800 when administered by the oral route. In fact, EM-800 administered orally is 2- to 3-fold more potent than ICI 182 780 injected s.c.