Ulmann and Silvestre (Appendix B6) reported on studies in ewes (Burgess, 1992) and monkeys (Wolf et al., 1989) showing that mifepristone induces uterine contractions and enhances the myometrial sensitivity to oxytocin at term. Newborn animals from mothers treated with mifepristone were normal. Very limited data in both animals and humans are available to corroborate this finding, and more studies are necessary on this use (see also Chapter 3).

Extensive discussions of the use of animal models in evaluating potential effects of new antiprogestins on breast cancer are presented in the paper by Horwitz (Appendix B9). Progesterone agonists increase the incidence of spontaneous mammary tumors in dogs and mice and, at physiologic levels, increase the growth of established tumors in some species (Horwitz, Appendix B9). Various animal models of hormone-dependent mammary cancer have been used to study the antiproliferative properties of progesterone antagonists and estrogen antagonists. These include rats that have chemically induced tumors and mice bearing transplanted tumor lines (Horwitz, Appendix B9). In these animal models, combined treatment with mifepristone and antiestrogens or gonadotropin-releasing hormone agonists produces high rates of tumor remission (Bakker et al., 1990). Other antiprogestins have been shown to have similar effects (Horwitz, Appendix B9). However, these models have limitations. For example, the nude mouse model has low progesterone-receptor levels and, despite hormone dependence, was found to be resistant to antiprogestins. Another difference is that the time of induction of breast cancer is weeks in rodent models versus years in human. This may explain why hormonal effects in cancer induction are more obvious or exaggerated in animal models than in humans. In women, only preliminary clinical studies have been reported on the potential use of antiprogestins in the treatment of advanced breast cancer, and there has been no report of the combined use of antiprogestins and antiestrogens as studied in the animal models described above (see Chapter 4). Although data from animal models are promising, long-term comparative human studies will be necessary to establish whether antiprogestins, or antiprogestins in combination with antiestrogens, might form a treatment modality for human breast cancer.

In conclusion, as for many drugs, animal models have been useful in understanding the mechanism of action and evaluating the potential of treatment modalities with antiprogestins. As would be expected, animal models are not always accurate predictors of the results in human beings. However, in the antiprogesterone data presented to and reviewed by the committee, particularly on mifepristone, animal models have been extremely useful in providing clues to the documented



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