RU486 (MIFEPRISTONE) - MECHANISMS OF ACTION AND CLINICAL USES

RU486 (mifepristone) has proved to be a remarkably active antiprogeste rone and antiglucocorticosteroid agent in human beings. The mechanism of action involves the intracellular receptors of the antagonized horm ones (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-induc ed transconformation differences in the ligand-binding domain. These p articularities have consequences at different steps of the receptor fu nction as compared with agonists. However, the reasoning cannot be lim ited to the RU486-receptor interaction, and, for instance, there is th e possibility of a switch from antagonistic property to agonist activi ty, depending on the intervention of other signaling pathways. It woul d be desirable to have derivatives with only one of the two antagonist ic properties (antiprogestin, antiglucocorticosteroid) in spite of sim ilarities between steroid structures, receptors involved, and responsi ve machineries in target cells. Clinically, the RU486-plus-prostagland in method is ready to be used on a large scale and is close to being a s convenient and safe as any medical method of abortion may be. The ea rly use of RU486 as a contragestive as soon as a woman fears a pregnan cy she does not want will help to defuse the abortion issue. Research should now be conducted to define an efficient and convenient contrace ptive method with RU486 or other antiprogestins. The usefulness of RU4 86 for obstetric indications, including facilitation of difficult deli very, has to be assessed rapidly. Gynecologic trials, particularly lei omyomata, should also be systematically continued. The very preliminar y results obtained with tumors, including breast cancers, indicate tha t further studies are necessary.