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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda
The committee reviewed results of a small initial clinical trial using an antiprogestin, mifepristone, in patients with meningiomas. About 25 percent (6 of 24 patients) had some improvement in their disease. Toxicities associated with daily chronic administration of the drug appeared tolerable. Although mifepristone appears to have some activity in recurrent or unresectable (inoperable) meningiomas, its clinical importance for treating a disease with a highly variable natural history remains to be defined. However, the lack of good alternative treatments for this group of patients and the mechanistic rationale make this an attractive treatment for further study.
Recommendation No. 19. A randomized Phase 3 trial will be required to define the role of antiprogestins in the management of patients with unresectable meningioma. Such a trial is ongoing in the Southwest Oncology Group. The committee recommends that these data be reviewed carefully to define directions for further research on this disease.
ANTIGLUCOCORTICOID EFFECTS OF ANTIPROGESTINS
Glucocorticoids are steroid hormones that are produced by the adrenal glands and that have biological effects in virtually every system of the body. Like other steroids (e.g., estrogens, progestins), glucocorticoids exert their actions through specific receptors in target cells. All antiprogestins identified to date can bind to glucocorticoid receptors and exert some glucocorticoid antagonist activity (antiglucocorticoid effects). In the context of most uses of antiprogestins, these antiglucocorticoid effects are undesirable. There are, however, diseases that involve excess adrenal production of glucocorticoid hormones (generically termed Cushing's syndrome) for which drugs that have antiglucocorticoid activity would be highly desirable. Indeed, the committee reviewed the literature on the use of mifepristone in the treatment of Cushing's syndrome, and found the results promising. For most of the documented uses of the drugs as antiprogestins, their antiglucocorticoid actions were clearly viewed as undesired side effects. For obvious medical reasons, it would be preferable to have separate classes of pure antiprogestins and of pure antiglucocorticoids that do not display any other endocrine effects.
Recommendation No. 20. Antiglucocorticoid effects are an unwanted property of existing antiprogestins. Therefore, the committee recommends expanded efforts to produce pure antiprogestins that would not display any other endocrine effects at therapeutic doses.