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 pot ent than ICI 182 780, the most potent known steroidal antiestrogen, at inhibiting estrone-stimulated uterine weight in ovariectomized mice ( half-maximal inhibitory daily sc doses of 0.2 and 2.0 mu g, respective ly). At maximal doses, however, both compounds lead to a similar maxim al 90% inhibition of estrone-stimulated uterine weight. A 10-fold high er activity of EM-800 compared with ICI 182 780 was also observed on e strone-stimulated vaginal weight, with maximal inhibitions of 96% and 90%, respectively, achieved by the two compounds. In addition, EM-800 injected sc or administered orally led to a marked loss of uterine and vaginal estrogen receptor levels measured by binding assay, whereas I CI 182 780 exerted no inhibitory effect on this parameter under the ex perimental conditions used. Comparable effects were observed when estr ogen receptor protein levels were measured by enzyme immunoassay. Afte r oral administration, EM-800 exerted maximal 83% and 88% inhibitions of uterine and vaginal weight, respectively, whereas maximal inhibitio ns limited to 51% and 67% were achieved with toremifene. This limited inhibition by toremifene of the stimulatory effect of estrone on uteri ne and vaginal weight is probably due to the intrinsic estrogenic acti vity of the compound. The present data also show that the steroidal an tiestrogen ICI 182 780 has less than 3% the activity of EM-800 when ad ministered by the oral route. In fact, EM-800 administered orally is 2 - to 3-fold more potent than ICI 182 780 injected sc.