RU486 (MIFEPRISTONE): Mechanisms of Action and Clinical Uses

Annual Review of Medicine - Tập 48 Số 1 - Trang 129-156 - 1997
F. Cadepond1,2, A Ulmann1,2, E.E. Baulieu1,2
1INSERM U33, 80 rue du Général Leclerc, Bicêtre Cedex, 94276 France
2Roussel-Uclaf BP9, Romainville, 92230 France

Tóm tắt

▪ 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 11β-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 also be systematically continued. The very preliminary results obtained with tumors, including breast cancers, indicate that further studies are necessary.

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Tài liệu tham khảo

10.1096/fasebj.5.9.1860615

10.1146/annurev.bi.63.070194.002315

Baulieu E-E. 1993.RU486—A decade on, today and tomorrow.InClinical Applications of Mifepristone RU 486 and Other Antiprogestins, ed. MS Donalson, D Dorflinger, SS Brown, LZ Benet, pp. 71–119. Washington: Natl. Acad. Inst. Med.

10.1016/S0040-4039(01)86260-2

Herrmann WL, 1982, C. R. Acad. Sci. Paris, 294, 933

10.1007/978-1-4684-1242-0_1

10.1016/0014-4827(83)90282-3

10.1073/pnas.81.12.3879

10.1210/jcem-59-1-25

Baulieu EE. 1985.RU486: an antiprogestin steroid with contragestive activity in women.InThe Antiprogestin Steroid RU486 and Human Fertility Control, ed. EE Baulieu, SJ Segal, pp. 1–25. New York: Plenum

Philibert D, Costerousse G, Gaillard-Moguilewsky M, et al. 1991.From RU38486 towards dissociated antiglucocorticoid and antiprogesterone.InAntihormones in Health and Disease, ed. MK Agarwal, 19:1–17. Basel: Karger

10.1016/0022-4731(88)90006-4

10.1097/00019616-199301000-00008

Chrousos GP, Lane L, Nieman LK, et al. 1989.Clinical applications of RU 486, a prototype glucocorticoid and progestin antagonist.InAdrenal and Hypertension: From Cloning to Clinic, ed. F Mantero, BA Scoggins, R Takeda, et al, pp. 273–84. New York: Raven

10.1126/science.2781282

10.1210/jc.78.2.375

10.1111/j.1749-6632.1995.tb31379.x

10.1111/j.1749-6632.1995.tb31398.x

10.1016/0960-0760(92)90110-5

10.1016/0039-128X(94)00067-M

10.1016/0003-9861(92)90083-9

10.1126/science.3283939

10.1096/fasebj.6.8.1592204

10.1210/edrv-11-2-201

10.1016/0092-8674(92)90234-4

10.1210/en.135.5.2183

10.1111/j.1432-1033.1985.tb08945.x

10.1126/science.1372753

10.1210/me.6.12.2071

10.1021/bi00158a012

Allan GF, 1992, J. Biol. Chem., 267, 19513, 10.1016/S0021-9258(18)41805-4

10.1210/me.6.10.1585

Baulieu EE, Catelli MG. 1989.Steroid hormone receptors and heat shock protein Mr 90,000 (hsp90): a functional interaction?InStress-Induced Proteins, ed. ML Pardue, JR Feramisco, S Lindquist, pp. 203–19. New York: Liss

10.1007/978-3-0348-5466-5_22

Lebeau MC, Binart N, Cadepond F, et al. 1993.Steroid receptor associated proteins: heat shock protein 90 and p59 immunophilin.InSteroid Hormone Receptors: Basic and Clinical Aspects, ed. VK Moudgil, pp. 261–80. Boston: Birkhäuser

10.1038/328624a0

10.1016/0022-4731(87)90001-X

10.1021/bi00426a017

Segnitz B, 1990, J. Biol. Chem., 265, 2789, 10.1016/S0021-9258(19)39871-0

10.1016/0039-128X(89)90142-6

10.1210/en.133.2.728

10.1016/0960-0760(95)00091-D

10.1021/bi00109a003

10.1038/336695a0

10.1073/pnas.90.10.4421

10.1016/0960-0760(93)90334-S

Beck CA, 1996, Science, 271, 1209, 10.1126/science.1996.271.5253.twis

10.1093/nar/19.6.1227

10.1038/324686a0

10.1073/pnas.91.24.11333

10.1210/me.8.5.568

10.1101/gad.9.11.1366

10.1210/me.8.9.1154

10.1146/annurev.ge.25.120191.000513

10.1002/j.1460-2075.1990.tb07613.x

10.1210/me.7.10.1244

10.1016/0022-4731(88)90109-4

10.1038/375377a0

10.1016/0960-0760(95)00095-H

Saatcioglu F, 1994, Cancer Biol., 5, 347

10.1089/dna.1993.12.695

10.1128/MCB.15.2.1005

10.1016/0960-0760(94)90190-2

McDonnell DP, 1994, J. Biol Chem., 269, 11945, 10.1016/S0021-9258(17)32664-9

10.1016/0039-128X(94)00001-S

Hoeck W, 1989, J. Biol. Chem., 264, 14396, 10.1016/S0021-9258(18)71692-X

Burnstein KL, 1990, J. Biol. Chem., 265, 7284, 10.1016/S0021-9258(19)39112-4

10.1016/S0015-0282(16)53174-4

10.1016/S0015-0282(16)59465-5

10.1056/NEJM198612183152501

10.1016/0010-7824(92)90126-E

10.1016/0010-7824(85)90115-5

10.1016/0952-3278(90)90097-5

10.3109/00016349209021052

Aubény E, 1991, C. R. Acad. Sci. Paris, 312, 539

10.1016/0140-6736(91)93212-R

10.1038/338110d0

Heard M, 1992, Lancet, 304, 914

Jost A, 1986, C. R. Acad. Sci. Paris, 303, 281

Lim BH, 1990, Lancet, 2, 257

10.1016/0010-7824(90)90129-J

10.1016/S0015-0282(16)59126-2

10.1016/S0140-6736(85)90575-6

10.1016/0002-9378(90)91193-G

10.1111/j.1471-0528.1991.tb15341.x

10.1111/j.1471-0528.1995.tb11360.x

10.1016/0002-9378(90)90821-N

10.1016/0010-7824(90)90069-8

1990, Am. J. Obstet. Gynecol., 160, 45

10.1016/S0140-6736(85)90785-8

10.1016/0002-9378(88)90528-5

Frydman R, 1992, Obst. Gynecol., 80, 972

Baulieu EE. 1991. InThe Abortion Pill, pp. 11–216. New York: Simon & Schuster

10.1056/NEJM199210083271501

10.1136/bmj.305.6859.927

10.1016/S0015-0282(16)60189-9

Bosc MJ, Germain G, Nicolle A, et al. 1985.The use of antiprogesterone compound RU486 to control timing of parturition in rats.InThe Antiprogestin Steroid RU486 and Human Fertility Control, ed. EE Baulieu, SJ. Segal, pp. 69–70. New York: Plenum

10.1016/0010-7824(87)90079-5

10.1016/0002-9378(91)90229-K

10.1016/S0015-0282(16)48198-7

Herrmann WL, Schindler AM, Wyss R1985.Effects of the antiprogesterone RU486 in early pregnancy and during the menstrual cycle.InThe Antiprogestin Steroid RU486 and Human Fertility Control, ed. EE Baulieu, SJ Segal, pp. 179–98. New York: Plenum

10.1210/jcem-61-3-484

10.1093/oxfordjournals.humrep.a136809

10.1093/oxfordjournals.humrep.a138458

10.1210/jc.74.3.565

10.1016/0028-2243(75)90021-0

10.1111/j.1471-0528.1991.tb13482.x

10.1210/jcem-63-6-1270

10.1210/jcem-66-3-508

10.1093/oxfordjournals.humrep.a137776

10.1210/jcem-65-6-1135

10.1016/S0015-0282(16)59944-0

10.1016/S0002-9378(87)80236-3

10.1093/oxfordjournals.humrep.a138022

10.1210/jcem-68-5-960

10.1210/jcem-60-1-156

10.1093/oxfordjournals.humrep.a136221

10.1016/S0015-0282(16)57478-0

10.1093/oxfordjournals.humrep.a138726

10.1016/S0015-0282(16)55200-5

10.1093/HUMREP/11.2.256

Baldi E, 1994, J. Androl., 12, 323, 10.1002/j.1939-4640.1991.tb01610.x

10.1073/pnas.91.2.529

Blackmore PF, 1991, J. Biol. Chem., 266, 18655, 10.1016/S0021-9258(18)55113-9

10.1111/j.1440-169X.1985.00223.x

10.1016/S0015-0282(16)57478-0

10.1210/jc.76.2.513

10.1016/S0015-0282(16)57678-X

10.1210/jcem-60-4-692

10.1210/er.13.2.146

10.1016/0960-0760(92)90360-U

10.1210/jc.75.3.865

Klijn JAGM, 1989, Cancer Res., 49, 2851

Romieu G, 1987, Bull. Cancer, 74, 455

10.1097/00002826-198412000-00016

10.1007/BF01406053

10.3171/jns.1987.66.4.0584

10.3171/jns.1991.74.6.0861

Haak HR, 1990, Lancet, 2, 124

10.1136/jnnp.55.6.486

10.3171/jns.1994.80.3.0527

10.1080/00332747.1990.11024523

10.1210/jcem-73-1-187

10.1210/jcem-71-6-1474

10.1007/BF00606640

10.1210/jcem-61-6-1009

10.1111/j.1365-2265.1988.tb03688.x

10.1210/jcem-61-3-536

10.7326/0003-4819-114-2-143

10.1016/S0140-6736(87)90796-3

10.1210/jcem-63-3-639

10.1056/NEJM199308053290607

10.1210/jc.80.2.379

10.1210/jcem-70-1-230

10.1073/pnas.92.8.3621

10.1111/j.1600-0897.1995.tb00949.x

10.1172/JCI117551

10.1016/0140-6736(91)92102-8

10.1016/0010-7824(92)90127-F

10.1159/000126474

10.1210/jcem-66-2-290

10.1176/ajp.143.1.129

Kling MA, 1989, Psychopharmacol. Bull., 25, 466

10.1159/000124900

10.1016/0006-8993(93)90042-L

10.1016/0278-5846(92)90109-R

Kling MA, 1989, Psychopharmacol. Bull., 25, 466

10.1530/acta.0.1270258

Grünfeld JP, 1987, Adv. Nephrol., 16, 53

Grünfeld JP, 1988, Kidney Int., 34, 24

10.1210/jc.77.4.902

Okada S, 1992, Am. Physiol. Soc., 262, 51106

10.1210/endo-124-4-1684

10.1128/AAC.36.11.2408

10.3109/02713688908997574

10.1001/archopht.1992.01080170125039

10.1210/jc.77.5.1388

10.1210/jcem-61-6-1009

10.1016/0014-5793(94)01186-9

Gruol DJ, 1994, Cancer Res., 54, 3088

Hospital M, 1972, Mol. Pharmacol., 8, 438

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Annual Review of Medicine

Tập 48 Số 1

129-156

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