RU 486 (mifepristone). A short overview of its mechanisms of action and clinical uses at the end of 1996.
RU 486 (mifepristone) has proved to be a remarkably active antiprogesterone and antiglucocorticosteroid agent in humans. The mechanism of action of RU 486 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 phenyl-aminodimethyl group in the 11 beta-position with a specific region of the receptor binding pocket, and RU 486-induced transconformation in the ligand binding domain. These properties have consequences at different steps of the receptor function as compared with agonists. However, this cannot be limited to the RU 486-receptor interaction; for instance, a switch from an antagonistic property to an agonist activity is possible, depending on the intervention of other signaling pathways. Derivatives with only one of the two antagonistic properties (antiprogestin, antiglucocorticosteroid) would be desirable in spite of similarities between the steroid structures, receptors involved, and responsive machineries in target cells. Clinically, the RU 486 plus prostaglandin method is ready to be used on a large scale, and is close to being as practical and safe as any medical method of abortion may be. The early use of RU 486, as a contragestive--that is, for use by a woman as soon as she 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 RU 486 or other antiprogestins. The usefulness of RU 486 for obstetrical indications, including facilitation of difficult delivery, has to be assessed rapidly. Gynecological trials, particularly in leiomyomata, should also be systematically continued. The very preliminary results obtained with tumors, including breast cancers, do indicate that further studies are necessary.
Baulieu
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INSERM U 33, Le Kremlin-Bicêtre, France. baulieu@kb.inserm.fr
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy; D003280:Contraceptives, Oral, Synthetic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005298:Fertility / Q000187:drug effects; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000378:metabolism; D006727:Hormone Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008600:Menstruation-Inducing Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D015735:Mifepristone / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D011247:Pregnancy; D011374:Progesterone / Q000037:antagonists & inhibitors / Q000378:metabolism
D003280:Contraceptives, Oral, Synthetic; D005938:Glucocorticoids; D006727:Hormone Antagonists; D008600:Menstruation-Inducing Agents; D015735:Mifepristone; D011374:Progesterone