RU486 (MIFEPRISTONE): Mechanisms of Action and Clinical Uses

Abstract

RU486 (mifepristone) has proved to be a remarkably active antiprogesterone and antiglucocorticosteroid agent in human beings. The mechanism of action involves the intracellular receptors of the antagonized hormones (progesterone and glucocorticosteroids). At the molecular level, the most important features are high binding affinity to the receptor, interaction of the phenylaminodimethyl group in the 11 beta-position with a specific region of the receptor binding pocket, and RU486-induced transconformation differences in the ligand-binding domain. These particularities have consequences at different steps of the receptor function as compared with agonists. However, the reasoning cannot be limited to the RU486-receptor interaction, and, for instance, there is the possibility of a switch from antagonistic property to agonist activity, depending on the intervention of other signaling pathways. It would be desirable to have derivatives with only one of the two antagonistic properties (antiprogestin, antiglucocorticosteroid) in spite of similarities between steroid structures, receptors involved, and responsive machineries in target cells. Clinically, the RU486-plus-prostaglandin method is ready to be used on a large scale and is close to being as convenient and safe as any medical method of abortion may be. The early use of RU486 as a contragestive as soon as a woman fears a pregnancy she does not want will help to defuse the abortion issue. Research should now be conducted to define an efficient and convenient contraceptive method with RU486 or other antiprogestins. The usefulness of RU486 for obstetric indications, including facilitation of difficult delivery, has to be assessed rapidly. Gynecologic trials, particularly in leiomyomata, should be systemically continued. The very preliminary results obtained with tumors, including breast cancers, indicate that further studies are necessary.

Mifepristone Repairs Region-Dependent Alteration of Synapsin I in Hippocampus in Rat Model of Depression

“…The steroid mifepristone is a remarkably active antiprogesterone and at high concentrations also an antagonist of GR action (Cadepond et al, 1997). The treatment of depression needs high dose of mifepristone, 600 or 1200 mg/ day.…”

“…With this procedure, the dose was swallowed completely and the stress caused to the animals was minimized, because control rats that received milk in the same way showed no stress-induced behavior change. Mifepristone is an antagonist of both progesterone receptor and GR (Cadepond et al, 1997). In the clinic, a low dose of 50 mg/ day mifepristone had an obvious antiprogesterone effect but no effects on cortisol, and only the high dose of 600 mg/day could antagonize GR (Belanoff et al, 2002).…”

Treatment of growth hormone excess in dogs with the progesterone receptor antagonist aglépristone

“…Progesterone receptor blockers such as aglépristone (RU 46534) and mifepristone (RU 38486) are competitive antagonists of the progesterone receptor [14,15]. Aglépristone is the first progesterone receptor blocker licensed for veterinary use and has been used efficiently to terminate pregnancy [16,17] and to induce parturition [18].…”

Demonstration of mixed properties of RU486 in progesterone receptor (PR)-transfected MDA-MB-231 cells: a model for studying the functions of progesterone analogues

“…These cells proved to be an excellent model for delineating the function of progesterone and its analogues. Progesterone was shown to induce remarkable growth inhibition and focal adhesion in the PR-transfected MDA-MB-231 cells ABC28 (Lin et al, 1999(Lin et al, , 2000.RU486 has proved to be a remarkable antiprogesterone and antiglucocorticoid agent in clinical applications since its birth some 20 years ago (Cadepond et al, 1997;Herrmann et al, 1982;Gaillard et al, 1983;Spitz and Chwalisz, 2000). In ABC28 cells, RU486 demonstrated mixed properties.…”

“…There has been increasing interest in the development of antiprogestins for both anti-neoplastic and obstetrical applications (Cadepond et al, 1997;Gravanis et al, 1985;Rocereto et al, 2000). However, some of the progesterone antagonists can have undesired agonist-like effects that are associated with cell, tissue and species specificity.…”