SCREENING FOR ANTIPROLIFERATIVE ACTIONS OF MIFEPRISTONE - DIFFERENTIAL ENDOMETRIAL RESPONSES OF PRIMATES VERSUS RATS

This laboratory has previously shown the capability of the antiprogest in, mifepristone, to noncompetitively inhibit estrogen-induced endomet rial proliferation in nonhuman primates. In the following study, use o f the rat uterine weight bioassay was compared against a primate (Maca ca fascicularis) uterine bioassay to identify the noncompetitive/antip roliferative effects of mifepristone. These uterine bioassays were con trasted for reasons of identifying a comparative-laboratory rodent mod el that could substitute for the need to use primate models in the scr eening of potential antiprogestins, thereby saving time, cost, and pri mate resources. Results of the primate experiment showed that mifepris tone decreased endometrial proliferation in a dose-dependent manner; i mportantly, this decrease occurred in the presence of sustained physio logic serum 17 beta-estradiol (E-2) levels. However, in the rat model, results showed that mifepristone altered uterine wet weight and blott ed weight values only in those animals receiving pharmacological doses of E-2 (p <0.05). Based on the results summarized herein, use of this rat uterine weight bioassay as a substitute for primate models is not recommended for screening and identification of ''interesting'' antip rogestins. Apparently the endometrial noncompetitive antiestrogenic/an tiproliferative effects of mifepristone, observed repeatedly in these laboratory primates, do not operate in the rat uterine tissue. (C) 199 8 Elsevier Science Inc. All rights reserved.