
 <b>Some Annotated Medical Journal Citations for Mifepristone [RU 486], an Anti-Progestogen Agent. </b>

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1. Environ Health Perspect 2000 Oct;108 Suppl 5:785-90 
<b>Regulation of vascular endothelial growth factor expression by estrogens and progestins.</b> 
Hyder SM, Huang JC, Nawaz Z, Boettger-Tong H, Makela S, Chiappetta C, Stancel GM. 
Department of Integrative Biology and Pharmacology, University of Texas-Houston Medical School, Houston, Texas 77225, USA. 

"<b>Estrogens increase the expression of vascular endothelial growth factor (VEGF) mRNA in the rodent uterus. This regulatory effect is rapid, beginning within 1 hr after hormone treatment, dose dependent, and blocked by the pure antiestrogen ICI 182,780. </b>The induction of the transcript is blocked by inhibitors of RNA but not of protein synthesis, and we have recently identified estrogen response elements in the VEGF gene. Collectively, these findings indicate that estrogens regulate uterine VEGF expression at the transcriptional level via the classical nuclear estrogen receptor pathway. Estrogen induction of VEGF occurs in the stromal layer of the rodent uterus, and estradiol induces expression of VEGF transcript levels in cultured human uterine stromal cells. Progestins also induce VEGF expression in the rodent uterus, although the effect is less marked and slower in onset than estrogenic effects. The effect of progestins is blocked by the antiprogestin mifepristone (RU-486), suggesting that it is also mediated by a classical nuclear receptor pathway. In addition, progestins regulate expression of VEGF mRNA and protein in cultured human T47-D breast cancer cells. The development of uterine leiomyomas is associated with exposure to ovarian sex steroids, abnormal uterine bleeding is commonly seen in patients with leiomyomas, and fibroids require an increased vascular supply for their growth. These observations suggest that VEGF and other angiogenic factors may represent potential targets for the treatment and prevention of uterine fibroids " 
&&url PMID: 11035983


2. Presse Med 1999 Dec 4;28(38):2123-31
<b>[Anti-progesterones] [Article in French]</b>
Sitruk-Ware R. Service d'Endocrinologie, Hopital Saint-Antoine, Paris. 

"THERAPEUTIC APPLICATIONS: Antiprogestins are a promising class of therapeutic agents in the field of reproductive health. Mifepristone (exRU486) remains the leading compound of this class and is the only one presently used in clinical practice. Beyond the main action of antiprogestins on human pregnancy, these compounds may prove useful in the treatment of uterine leiomyomas and endometriosis, and for contraception. IN CANCEROLOGY: Rare tumors such as meningiomas or leiomyoarcomas expressing progesterone receptors may [perhaps, ed.] be successfully treated with these antihormones. MAIN INDICATIONS: The main characteristics of the different antiprogestins discovered so far are addressed and the key results from the large clinical studies conducted with mifepristone are described here for indications where the product is approved for clinical use: medical termination of pregnancy during the first trimester, cervical dilatation prior to surgical termination of pregnancy, preparation for prostaglandin action in the therapeutic termination of pregnancy beyond the first trimester, labor induction in case of foetal death in utero." &&url PMID: 10613204 


3.J Soc Gynecol Investig 1998 Nov-Dec;5(6):334-8 
<b>Inhibition of endometrial cancer cell lines by mifepristone (RU 486)</b>.  
Schneider CC, Gibb RK, Taylor DD, Wan T, Gercel-Taylor C. 
Department of Obstetrics and Gynecology, University of Louisville School of Medicine, Kentucky 40202, USA. 
&&url PMID: 9824816 


4. Zhonghua Fu Chan Ke Za Zhi 1998 Aug;33(8):490-2 
<b>[A clinical control study on the treatment of uterine leiomyoma with gonadotrophin releasing hormone agonist or mifepristone]. [Article in Chinese]</b>
 Zeng C, Gu M, Huang H. 
4th Municipal Hospital, Wuhan.
 
"To compare the results and side effects in treating uterine leiomyoma with gonadotrophin releasing hormone agonist (GnRH-a) or mifepristone. ... 75 patients with uterine leiomyoma who had clinical symptoms ... were divided into two groups. The GnRH-a group (30 patients) was treated by injection of GnRH-a 150 micrograms/day subcutaneously for three months, and the mifepristone group (45 patients) was treated by mifepristone 12.5 mg/day po for three months. ... The clinical symptoms improved obviously in both groups. The volume of leiomyoma reduced 20.0% or more in 90.0% (27/30) of the patients in GnRH-a group, while it was 91.1% (41/45) in mifepristone group. However, the recurrent rates were 40.0% and 17.8% in the 2 groups. ... It suggested that mifepristone is a more practical and hopeful drug in treating uterine leiomyoma." 
&&url PMID: 10806751 


5. Cancer Res 1998 Feb 1;58(3):392-5 
<b>Progestin regulation of vascular endothelial growth factor in human breast cancer cells.</b> 
Hyder SM, Murthy L, Stancel GM. 
Department of Integrative Biology, Pharmacology and Physiology, University of Texas Health Sciences Center-Houston,  

"Vascular endothelial growth factor (VEGF) is a potent angiogenic factor associated with the degree of vascularity, progression, and metastasis of breast cancer, and cases of this disease with increased vascular density have a poor prognosis. We show that in T47-D human breast cancer cells, progesterone induces a dose-dependent increase of 3-4-fold in media VEGF levels, with a maximum response occurring at a concentration of 10 nM. This effect is blocked by the antiprogestin RU 486. ..." 
&&url PMID: 9458078 


6.Fertil Steril 1997 Dec;68(6):967-76 
<b>Mifepristone (RU486): a review.</b> 
Mahajan DK, London SN. 
Department of Obstetrics and Gynecology, Louisiana State University School of Medicine, Shreveport 71130, USA. 

"Mifepristone effectively blocks P receptors in the placenta, resulting in the termination of pregnancy. In addition, it has been used in the treatment of leiomyomata, endometriosis, advanced breast cancer, and meningioma. It is a powerful tool to study the molecular action of P and in the future may be used as an estrogen-free contraceptive." &&url PMID: 9418681


7. Hum Reprod Update 1995 Jan;1(1):19-34 
<b>Clinical uses of antiprogestogens.</b> 
Van Look PF, von Hertzen H. 
Special Programme, Development and Research Training in Human Reproduction, World Health Organization, Geneva, Switzerland. 

"Antiprogestogens, which block the action of progesterone at the cellular level through binding to the progesterone receptor, are proving to be one of the most significant developments in endocrinology in recent years. ... Most of the clinical research to date has focused on the use of mifepristone given in combination with prostaglandin for termination of early pregnancy.... In fertility regulation, the sequential combination regimen of mifepristone plus prostaglandin as used for inducing abortion has proved to be effective also for menses induction and can be expected to be an efficacious once-a-month contraceptive. Mifepristone alone, without adjuvant prostaglandin, has yielded promising results as an anti-implantation agent and in emergency contraception. Other potential uses include once-a-week contraception, ovulation inhibition (in a sequential regimen with a progestogen), and as a daily mini-pill. Mifepristone, and other antiprogestogens for which biological data have been reported also bind to the cellular receptors for glucocorticoid hormones and, consequently, possess antiglucocorticoid in addition to their antiprogestational activity. Because of this antiglucocorticoid effect, mifepristone has been employed successfully in the palliative treatment of hypercortisolism due to Cushing's syndrome, and its use has been proposed for treating certain forms of depression and of glaucoma, and in wound healing. However, for scientific and practical reasons, it would be preferable if molecules were developed that have only the antiprogestational or the antiglucocorticoid activity rather than both."
&&url PMID: 9080204 


8. Am J Obstet Gynecol 1994 Jun;170(6):1623-7; discussion 1627-8 
<br>The effects of RU 486 and leuprolide acetate on uterine artery blood flow in the fibroid uterus: a prospective, randomized study.</b> 
Reinsch RC, Murphy AA, Morales AJ, Yen SS. 
Department of Obstetrics and Gynecology, Kaiser Permanente, University of California, San Diego 92103. 

" We noted a significant decrease in uterine volume compared with pretreatment in both groups at 3 months. There was no significant decrease between groups. ...: Both RU 486 (25 mg daily) and leuprolide acetate (3.75 mg monthly) are effective in decreasing blood flow to the uterus (increasing resistive index) and decreasing uterine volume at 3 months. A significant decrease in uterine artery blood flow may provide a mechanism for the decrease in uterine size and the decrease in uterine blood loss at the time of surgery." 
&&url PMID: 8203418 


9. Curr Opin Obstet Gynecol 1994 Jun;6(3):269-78 
<b>RU486: pharmacology and potential use in the treatment of endometriosis and leiomyomata uteri.</b> 
Murphy AA, Castellano PZ. 
Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia. 

"RU486 has been shown to relieve pelvic pain associated with endometriosis and to decrease American Fertility Society endometriosis scores. Uterine leiomyomata show a significant reduction in size after administration of RU486 for 3 months. Although much research remains to be carried out, RU486 appears promising as alternative therapies for these diseases." 
&&url PMID: 8038415 
 

10. Presse Med. 1999 Dec 4;28(38):2123-31.  
<b>[Anti-progesterones] [Article in French]</b>
 Sitruk-Ware R.
Service d'Endocrinologie, Hopital Saint-Antoine, Paris.

"Antiprogestins are a promising class of therapeutic agents in the field of reproductive health. Mifepristone (exRU486) remains the leading compound of this class and is the only one presently used in clinical practice. Beyond the main action of antiprogestins on human pregnancy, these compounds may prove useful in the treatment of uterine leiomyomas and endometriosis, and for contraception." 
"IN CANCEROLOGY: Rare tumors such as meningiomas or leiomyosarcomas expressing progesterone receptors may be successfully treated with these antihormones. 
"MAIN INDICATIONS: The main characteristics of the different antiprogestins discovered so far are addressed and the key results from the large clinical studies conducted with mifepristone are described here for indications where the product is approved for clinical use: medical termination of pregnancy during the first trimester, cervical dilatation prior to surgical termination of pregnancy, preparation for prostaglandin action in the therapeutic termination of pregnancy beyond the first trimester, labor induction in case of foetal death in utero."
&&url PMID: 10613204  


11. Diskussionsforum Med Ethik. 1992;(6-7):XXXVIII-XLIII. 
<b>[Mifepristone (RU 486)]</b> [Article in German]
Bonelli RM.

"The antiprogestin RU 486 converts the early pregnant uterus by increasing the sensitivity of the myometrium to prostaglandin (PG). These effects of antiprogestin have resulted in the development of nonsurgical procedures to abort embryos based on a combination of RU 486 and different PG-analogues administered vaginally or intramuscularly. RU 486 also has a softening effect on the cervix which may be used as pretreatment in second and third trimester abortions. The effects, mode of action, dangers, and the many other postulated clinical implications (like breast cancer, meningioma, ectopic pregnancy, fetal death in utero, induction of labour, initiation and promotion of lactation, endometrial or ovarian cancers, leukemia, Cushing's syndrome, uterine adenomyosis, acute uremia, leiomyosarcoma, hypertension, etc.) are discussed."
&&url PMID: 1514299  


12. Int J Cancer. 1989 Dec 15;44(6):1034-40. 
<b>The influence of glucocorticoids on the growth of a human leiomyosarcoma cell line SK-LMS-1.</b>
Madsen WE, Gupta TK, Walker MJ.
Department of Surgery, University of Illinois College of Medicine, Cook County Hospital, Chicago.

"A cell line derived from a human leiomyosarcoma, SK-LMS-I, has cystolic ... glucocorticoid receptor, by Scatchard analysis of tumors grown in male athymic mice. Tumor growth of SK-LMS-I cells in male athymic mice is inhibited by daily s.c. injection of DEX 5 micrograms, DEX 25 micrograms, DEX 5 micrograms with 5 mu RU-486 and 5 micrograms RU-486. In sharp contrast, in vitro, glucocorticoid markedly stimulates the growth (as determined by cell number) of SK-LMS-I cells, principally at higher cell densities (days 10-21 of growth carried on over a 21- to 23-day period), the greatest stimulation being seen with DEX 10(-6) to 10(-8) M, and no stimulation being seen with DEX 10(-9) and 10(-10) M. In vitro, glucocorticoids with higher affinity for the GR stimulate growth, steroids with lower affinity inhibit growth. No alterations in cell-cycle distribution (percent G0/G1, S, or G2/m) could be found by flow cytometric analysis of glucocorticoid-stimulated asynchronously growing cultures. Single, isolated, untreated SK-LMS-I cells form colonies in soft agar with an efficiency of 1.78 +/- 0.10%. Pre-treatment of cells with DEX 10(-7) M increases this to 3.24 +/- 0.17%, while cells pre-treated with both DEX 10(-7) M RU-486 10(7) M form colonies with the same efficiency as untreated cells. Glucocorticoids have inhibitory effects on in vivo growth and stimulatory effects on in vitro growth of a GR-positive human leiomyosarcoma cell line.
&&url PMID: 2606572  
