Clinical Applications of Mifepristone (RU486) and Other Antiprogestins Assessing the Science and Recommending a Research Agenda (1993) / Chapter Skim
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Other Therapeutic Uses of Antiprogestins
Other Therapeutic Uses of Antiprogestins
Pages 36-51
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From page 36... ...
The most typical symptomatic complaints associated with endometriosis include chronic pelvic pain, dysmenorrhea (painful menses) , dyspareunia (painful intercourse)
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(1989) , who observed that the administration of mifepristone to female monkeys treated with human menopausal gonadotropin and human chorionic gonadotropin resulted in the genesis of an atrophic to weakly proliferative endometrium on menstrual cycle day 25, despite serum estradiol concentrations in excess of 300 pa/ml.
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Bone mineral density measurements of the lumbar spine and femur revealed no adverse effect. An initial increase in the circulating levels of LH and testosterone was noted in the first month of treatment.
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Leiomyomas, which may be single or multiple and highly variable in size, are the most common pelvic tumor recognized, occurring with the highest frequency during the fifth decade of a woman's life. Although the precise cellular mechanism underlying the pathogenesis of leiomyomas remains unknown, there is little question about the hormonal dependence of this condition.
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(1993~. The investigators examined the effects of daily administration of mifepristone at a dose of 50 mg for three months on 10 patients with uterine leiomyomas and regular menstrual cycles.
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Measures of outcome should not be limited to pain relief alone, but should also address the likelihood of improving fertility. Once such studies are completed, randomized clinical trials should be undertaken to compare the safety and efficacy of mifepristone and other antiprogestins with current therapies for the treatment of endometriosis and uterine leiomyomas.
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From page 42... ...
Blockade of this mitogenic effect was described as a potential strategy for breast cancer prevention. On a molecular basis, there are a number of differences among progesterone receptors when bound to various antiprogestins (some antiprogestin-receptor complexes bind to DNA, and others do not)
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From page 43... ...
Data on down-regulation of tenascin, an extracellular matrix glycoprotein of tumor stroma, in rat mammary tumors provide additional support for the induction of terminal differentiation as an underlying mechanism of growth inhibition by onapristone. Interestingly, although ovariectomy and antiestrogen therapy were associated with growth inhibition in this model, neither was associated with decreased expression of tenascin (Vollmer et al., 1992~.
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From page 44... ...
In a second study, 11 postmenopausal patients received mifepristone doses of 200 to 400 mg daily as second-line treatment following tamoxifen (Michna et al., 1989; Bakker et al., 1990; Horwitz, Appendix By. 2Typical criteria for partial response require a 50 percent reduction in the sum of the products of the perpendicular diameters of the measured lesion.
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suggest that cautious observation will be required prior to clinical trials in early breast cancer or prevention. Substantial clinical activity and acceptable toxicity in advanced disease patients would be required before one could seriously consider using antiprogestins as an adjuvant treatment for breast cancer and certainly prior to their introduction for the chemoprevention of breast cancer.
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Resistance Eventually all advanced breast cancers become hormone independent and increasingly resistant to any subsequent therapy. It is this development of resistance that limits the potential utility of antiprogestins and other endocrine therapies for the treatment of advanced disease.
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Whether this antitumor activity will be unique among the many other available endocrine therapies for breast cancer remains to be seen. There are at present too few clinical data to assess adequately the clinical potential of antiprogestins in the treatment of metastatic breast cancer, much less to assess their potential applications for adjuvant therapy or chemoprevention.
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From page 48... ...
Such studies should include a. further characterization of progesterone receptors, including the natural A and B forms, as well as possible genetic mutants, and their distribution in normal and malignant tissue; this will be important for the rational use of antiprogestins in future clinical trials b.
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From page 49... ...
Toxicities associated with daily chronic administration appeared tolerable and included fatigue, hot flashes, breast enlargement and tenderness, thinning of hair, and rash. Amenorrhea occurred in the three premenopausal patients; however, menses resumed in two patients following cessation of therapy.
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REFERENCES Bakker, G.H., Setyono-Han, B., et al. Endocrine and antitumor effects of combined treatment with an antiprogestin and antiestrogen or luteinizing hormone-releasing hormone agonist in female rats bearing mammary tumors.
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From page 51... ...
Noncompetitive antiestrogenic effect of RU 486 in blocking the estrogen-stimulated luteinizing hormone surge and the proliferative action of estradiol on endometrium in castrate monkeys. Fertility and Sterility 52:10551060, 1989.
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