Clinical Applications of Mifepristone (RU486) and Other Antiprogestins Assessing the Science and Recommending a Research Agenda (1993) / Chapter Skim
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B1. 1993: RU 486--A Decade on Today and Tomorrow
B1. 1993: RU 486--A Decade on Today and Tomorrow
Pages 71-119
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From page 71... ...
this development was based on the physiological concept that sex steroid hormones exert negative feedback control on ovulahon. With prowess in steroid chemistry orally acme compounds that mimicked the action of endogenous steroids were developed (~erassC 1970\ In the 1960s and 1970s, ~ became dear that the livable contraceptive methods did not completely meet the needs of women and they famines; nor would they gone have a sufficient demographic impact to 1~fephstone (RU 38486, 175-hydroxy-llp-(~-dimethylaminophenyLl)
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From page 72... ...
During those decades, ideas for new methods of contraception emerged as biology became focused more on the cellular and molecular elements of regulation of the reproductive system. The hormone-responsive proteins of target cells in the reproductive tract (termed receptors)
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From page 73... ...
Because steroids are rigid molecules of well-defined conformation, as the high-affinity binding site of the receptor should be, it seemed logical to expect that a breakthrough in the hormone antagonism field would occur first in the antisteroid field. Initially, steroid receptors were detected by the binding of a traceable (radiolabeled)
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From page 74... ...
However, the presence or absence of the third phenyl ring is not the critical factor for determining binding affinity since 4-hydroxytamoxifen, with an additional hydroxyl on the ring A equivalent of the tamoxifen molecule, mimicking the 3-hydroxyl group of estradiol, is a compound with high affinity for the receptor and has a resulting strong antiestrogenic effect ("pure" antagonist with no agonist activity in the chick) (Sutherland et al., 1977~.
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From page 75... ...
In fact, there was no adequate theoretical reason to equate the quantitative notion of high affinity with the qualitative property of hormone antagonism. The latter was predictably due to specific conformational changes of receptor domains that are involved in the transcription activation functions (TAF)
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From page 76... ...
, continued with the observation of the antiglucocorticosteroid activity of RU 486, and thereafter the demonstration of its antiprogesterone property. The decision to test it for human abortion was made after the endocrinological and pharmacological studies performed by Daniel Philibert and colleagues.
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From page 77... ...
RU 40555 (see Figure B1.4 for structure of this and other compounds discussed in this section) does not bind to the orosomucoid and has a shorter half-life, which may be of interest for kinetic assessment of the hypothalamus-pituitaryadrenal axis in clinical endocrinology (Bertagna et al., 1984; Gaillard et al., 1984~.
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From page 78... ...
Curiously, 17~-acetyl,16`x-ethyl derivatives of 116-phenylsubstituted steroids are progestin agonists (Cook et al., 1992~. The Schering group has synthesized lilopristone, with a 17,B side chain slightly different from that of RU 486; it has less antiglucocorticosteroid activity and higher binding to the androgen receptor.
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From page 79... ...
Transcription activation was quantitated from normalized CAT assays in HeLa transiently-transfected cells with the MM1V-CAT reporter gene and the human progesterone-receptor (hPR) expression vector hPR1 in the presence of the various compounds.
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From page 80... ...
Ligands for the hPR may generate three distinct types of TAF2-dependent transcriptional responses: they act as agonists with no antagonistic potential or as antagonists with no agonistic potential, or they may generate a mixed response, since they both activate and antagonize transcription activation. HeLa cells were transiently transfected with a reporter gene and a progesterone response element and exposed to the steroids in the absence or presence of RU 27987 (Figure B1.5)
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From page 81... ...
Shown in Table B1.1 and Figure B1.8 are several steps involved in the intracellular mechanism of steroid hormone and antihormone action. Progesterone, cortisol, and their cognate synthetic agonists and antagonists seem to enter target cells freely and appear not to be
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From page 82... ...
The GR and PR, like other steroid hormone receptors, form heterooligomeric, non-DNA binding, "nontransformed" 8S complexes that include receptor-associated proteins (Baulieu et al., 1989; Lebeau et al., 1993~. The most studied of these proteins are a heat shock protein of MW = 90,000 Da (hsp90)
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From page 83... ...
This disposition obliterates the DNA binding to the DBD (Baulieu and Catelli, 1989) , and hsp90-receptor complexes do not bind to DNA (Bourgeois et al., 1984~.
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From page 84... ...
Receptor transconformation following ligand binding determines the appropriate interaction of the receptor with TFs1IFs. Receptor transconformation is also likely to be involved in inducing chromatin changes, which themselves eventually cooperate in hormone action by allowing or inhibiting TF/TIF function.
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From page 85... ...
, as observed with the 8S ER (Redeuilh, 1987b) , and thus precedes DNA binding and activation of the transcription function.
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From page 86... ...
Moreover, from these results, it has been postulated that the C-terminal region of the receptor could act as an inhibitor of TAFT in the absence of ligand or when bound to RU 486, with the negative function being released in the presence of an agonist (Vegeto et al., 1992~. Heat Shock Protein Binding Transconformation of the LBD is probably involved in the modulation of hsp90 interaction with the receptor, and the in vitro stabilization of hsp90-containing 8S complexes after RU 486 binding has been demonstrated for RU 486-bound GR (Groyer et al., 1987)
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From page 87... ...
Since RU 486 binding to DNA is not followed by an effect on transcription, the RU 486-receptor complexes are unproductive, possibly due in part to a defect in chromatin structure and/or interaction with TF/TIF. It has been suggested that the onaprisone-receptor complex does not have the ability to bind to HREs (Klein-Hi/pass et al., 1991~.
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From page 88... ...
In addition, the binding of NF1, a nonspecific transcription factor, to its DNA site in the MM TV system does not take place after RU 486 binding as it does after the binding of an agonist. Gene Transcriplion Activation of gene transcription is regarded as the major mode of action of steroid hormones, mediated by two transcription activation functions of the receptor (Evans, 1988; Lees et al., 1989; Tora et al., 1989; Gronemeyer, 1991~.
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From page 89... ...
Hormone action involves a number of phenomena that are narrowly connected at least temporally: release of hsp90 and other associated proteins, dimerization of the receptor, DNA binding and chromatin changes, and interaction with TFs/TIFs. The net result may be to increase or decrease gene transcription, and depends in part on specific HREs and TF(s)
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From page 90... ...
) Granulosa cells Tubal transport En d o me trium Estrogen-dependent growth Maturation Decidua Implantation Immunological reaction Myometrial contractility Cervical maturation Maintenance of pregnancy Labor/delivery Placenta hormones Activation example, studies in the uterus, endometrium, myometrium, and cervical tissue directly relate to the use of RU 486 in fertility control.
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From page 91... ...
Sexual behavior can be modified by the antiprogestin effect of RU 486 (Brown and Blaustein, 1986; Pleim, 1990~. In breast cancer cells, RU 486 inhibits P-induced transcriptional activity, which leads to the synthesis of fatly acid synthetase but, surprisingly, it stabilizes the mRNA of this enzyme (Chalbos et al., 1991~.
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From page 92... ...
REPRODUCTIVE MEDICINE (TABLE B1.4) Voluntary Early Pregnancy Interruption On the basis of animal experiments, we expected RU 486 to meet the recognized need for an efficient medical means of early abortion, to be safer than a surgical technique, and to be relatively convenient and cheap (no anesthesia, no operating room)
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From page 93... ...
Iuteolys~s = ~ CONTRACTILITY vaglaa FIGURE B1.10 Physiopharmacological mechanism of action of RU 486 on the implanted blastocyst. Temporally, the antiprogesterone effect of RU 486 comes first, and then an increase in PG concentration and action, fol lowed by a decrease in hCGsustained corpus luteum function.
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From page 94... ...
Coincidentally, the death of a patient (having received intramuscular Sulprostone) was reported at the same time as the first trial of RU 486 plus orally active misoprostol (a POE derivative)
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From page 95... ...
1993: RU 486 A DECADE ON TODAY AND TOMORROW TABLE B1.6 Interruption of Early Pregnancy with RU 486 and One or Two Doses of Misoprostol 95 Number of Successesa Number of Failuresb Treatment Total (TO of total) (% of total)
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From page 96... ...
In France, voluntary pregnancy interruption is legally permitted until 12 weeks of amenorrhea. When women have passed beyond the current legal limit for RU 486 plus misoprostol treatment (seven weeks)
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From page 97... ...
exposure need to be assessed carefully (Weinstein et al., 1991~. Until the absolute safety of antiprogestins is demonstrated in cases where there is a medical indication for labor induction, its use for convenience should be forbidden.
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From page 98... ...
Note also that the process of implantation is not instantaneous and takes several days during the last week of the fertile menstrual cycle, just before the time at which menses would occur. Coincidentally, the development of the embryo is characterized by the streak (a marker indicating that an individual embryo has been formed, and there is no further risk of twins)
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From page 99... ...
Research needs to be pursued in order to determine the appropriate dose, and whether the administration can be repeated, how many times, and for how long, a possibility that appears rather remote because of probable changes in menstrual cyclicity. Late Lutea/ Phase Administration (Occasiona/ Use)
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From page 100... ...
The provisional name "endometrial contraception" is given to the continuous exposure to a very low dose of RU 486. This may modify the genital tract in such a way that implantation and possibly fertilization do not occur, while ovulation and the pattern of estrogen and progesterone secretion are unchanged, and adrenal function is unmodified.
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From page 101... ...
We submit that this method with ovulation suppression will be more difficult to implement relative to continuous administration of a very low dose. In conclusion, there is already hope, not to say certainty, for an occasional contraceptive/contragestive method, and "endometrial contraception" is a very appealing possibility.
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From page 102... ...
These effects suggest that the compound may be useful for the treatment of endometriosis (Kettel et al., 1991~. As expected, in women, RU 486 suppressed ovulation and menstrual cycle, and brought about an increase of LH (with augmented pulse amplitude but not frequency)
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From page 103... ...
RU 486 inhibits the growth of breast cancer cells in a Pit-dependent manner (Bardon et al., 1985; Thomas and Monet, 1992~. Interestingly, one may demonstrate (1)
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From page 104... ...
The spontaneous variety of evolution of these tumors makes a definitive evaluation of the beneficial effects very difficult, even though definite, sometimes spectacular improvement has been observed in about onethird of available reports. Instead of RU 486, an antiprogesterone without antiglucocorticosteroid activity would be welcomed.
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From page 105... ...
The long-term use of RU 48~for instance, to treat tumorsmay be improved if a compound blocking steroid biosynthesis is given simultaneously. In breast cancer this could be an antiaromatase because production of estrogens increases when adrenal androgen hypersecretion occurs with RU 486 treatment.
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From page 106... ...
The most cruel, breast cancer, should be first on the list of trials. Again, this may take time and money, but there already are clues that cannot be neglected.
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From page 107... ...
RU486, a progestin and glucocorticoid antagonist, inhibits the growth of breast cancer cells via the progesterone receptor. Journal of Clinical Endocrinology and Metabolism 60:692 697, 1985.
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From page 108... ...
Cell surface-binding sites for progesterone mediate calcium uptake in human sperm. Journal of Biological Chemistry 266:1865518659, 1991.
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From page 109... ...
Bourgeois, S., Mester, J., and Baulieu, E.E. DNA binding properties of glucocorticosteroid receptors bound to the steroid antagonist RU 486.
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From page 110... ...
Studies on the mechanisms of action of progesterone antagonists. Journal of Steroid Biochemistry 25:835~45, 1986.
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From page 111... ...
on the hypothalamic-hypophyseal-ovarian-endometrial axis during the luteal phase of the menstrual cycle. Journal of Clinical Endocrinology and Metabolism 66:508-517, 1988.
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From page 112... ...
Effects of the antiprogesterone RU486 in early pregnancy and during the menstrual cycle. Pp 179-198 in The Antiprogestin Steroid RU486 and Human Fertility Control.
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From page 113... ...
Klijn, J.G.M., Bakker, G.H., Setyono-Han, B., et al. Antiprogestin treatment of experimental and clinical breast cancer.
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From page 114... ...
Novel antiprogestins ORG 31806 and 31710: Interaction with mammalian progesterone receptor and DNA binding of antisteroid receptor complexes. Journal of Steroid Biochemistry and Molecular Biology 42:69~704, 1992.
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From page 115... ...
Antiprogestin-receptor complexes: Differences in the interaction of the antiprogestin RU38486 and the progestin R5020 with the progesterone receptor of human breast cancer cells. Biochemical and Biophysical Research Communications 135:9~97, 1986.
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From page 116... ...
Pratt, W.B., Jolly, D.J., Pratt, D.V., et al. A region in the steroid binding domain determines formation of the non-DNA binding, 9S glucocorticoid receptor complex.
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From page 117... ...
Schweizer-Groyer, G., Cadepond, F., Groyer, A., et al. Stimulation of specific transcription and DNA binding studies suggest that in vitro transformed RU486-glucocorticosteroid receptor complexes display agonist activity.
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From page 118... ...
Progesterone transcriptionally regulates the ,82-adrenergic receptor gene in pregnant rat myometrium. Journal of Biological Chemistry 267:797~7978, 1992.
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From page 119... ...
Progesterone antagonist (RU 486) for cervical dilatation, labor induction, and delivery in monkeys: Effectiveness in combination with oxytocin.
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