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James T Dalton - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetic drug interactions of the selective androgen Receptor Modulator gtx 024 enobosarm with itraconazole rifampin probenecid celecoxib and rosuvastatin
Investigational New Drugs, 2016Co-Authors: Christopher C Coss, Amanda Jones, James T DaltonAbstract:GTx-024 (also known as enobosarm) is a first in class selective androgen Receptor Modulator being developed for diverse indications in oncology. Preclinical studies of GTx-024 supported the evaluation of several potential drug-drug interactions in a clinical setting. A series of open-label Phase I GTx-024 drug-drug interaction studies were designed to interrogate potential interactions with CYP3A4 inhibitor (itraconazole), a CYP3A4 inducer (rifampin), a pan-UGT inhibitor (probenecid), a CYP2C9 substrate (celecoxib) and a BCRP substrate (rosuvastatin). The plasma pharmacokinetics of GTx-024, its major metabolite (GTx-024 glucuronide), and each substrate were characterized in detail. Itraconazole administration had no effect on GTx-024 pharmacokinetics. Likewise, GTx-024 administration did not significantly change the pharmacokinetics of celecoxib or rosuvastatin. Rifampin administration had the largest impact on GTx-024 pharmacokinetics of any co-administered agent and reduced the maximal plasma concentration (Cmax) by 23 % and the area under the curve (AUC∞) by 43 %. Probenecid had a complex interaction with GTx-024 whereby both GTx-024 plasma levels and GTx-024 glucuronide plasma levels (AUC∞) were increased by co-administration of the UGT inhibitor (50 and 112 %, respectively). Overall, GTx-024 was well tolerated and poses very little risk of generating clinically relevant drug-drug interactions.
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the selective androgen Receptor Modulator gtx 024 enobosarm improves lean body mass and physical function in healthy elderly men and postmenopausal women results of a double blind placebo controlled phase ii trial
Journal of Cachexia Sarcopenia and Muscle, 2011Co-Authors: James T Dalton, Kester G Barnette, Casey E Bohl, Michael L Hancock, D Rodriguez, Shontelle Dodson, Ronald A Morton, Mitchell S SteinerAbstract:Background Cachexia, also known as muscle wasting, is a complex metabolic condition characterized by loss of skeletal muscle and a decline in physical function. Muscle wasting is associated with cancer, sarcopenia, chronic obstructive pulmonary disease, end-stage renal disease, and other chronic conditions and results in significant morbidity and mortality. GTx-024 (enobosarm) is a nonsteroidal selective androgen Receptor Modulator (SARM) that has tissue-selective anabolic effects in muscle and bone, while sparing other androgenic tissue related to hair growth in women and prostate effects in men. GTx-024 has demonstrated promising pharmacologic effects in preclinical studies and favorable safety and pharmacokinetic profiles in phase I investigation.
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characterization of the in vitro metabolism of selective androgen Receptor Modulator using human rat and dog liver enzyme preparations
Drug Metabolism and Disposition, 2006Co-Authors: Wenqing Gao, Casey E Bohl, Jun J Yang, Duane D Miller, James T DaltonAbstract:Compound S4 [S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide] is a novel nonsteroidal selective androgen Receptor Modulator that demonstrates tissue-selective androgenic and anabolic effects. The purpose of this in vitro study was to identify the phase I metabolites, potential species differences in metabolism, and the cytochromes P450 (P450s) involved in the phase I metabolism of S4 using 14C-S4, recombinant P450s, and other liver enzyme preparations from human, rat, and dog. The major phase I metabolism pathways of S4 in humans were identified as deacetylation of the B-ring acetamide group, hydrolysis of the amide bond, reduction of the A-ring nitro group, and oxidation of the aromatic rings, with deacetylation being the predominant pathway observed with most of the enzyme preparations tested. Among the major human P450 enzymes tested, CYP3A4 appeared to be one of the major phase I enzymes that could be responsible for the phase I metabolism of S4 [Km = 16.1 μM, Vmax = 1.6 pmol/(pmol · min)] in humans and mainly catalyzed the deacetylation, hydrolysis, and oxidation of S4. In humans, the cytosolic enzymes mainly catalyzed the hydrolysis reaction, whereas the microsomal enzymes primarily catalyzed the deacetylation reactions. Similar phase I metabolic profiles were observed in rats and dogs as well, except that the amide bond hydrolysis seemed to occur more rapidly in rats. In summary, these results showed that the major phase I reaction of S4 in human, rat, and dog is acetamide group deacetylation.
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selective androgen Receptor Modulator treatment improves muscle strength and body composition and prevents bone loss in orchidectomized rats
Endocrinology, 2005Co-Authors: Wenqing Gao, Christopher C Coss, Duane D Miller, Peter J Reiser, Mitch A Phelps, Jeffrey D Kearbey, James T DaltonAbstract:The partial agonist activity of a selective androgen Receptor Modulator (SARM) in the prostate was demonstrated in orchidectomized rats. In the current study, we characterized the full agonist activity of S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide (a structurally related SARM referred to in other publications and hereafter as S-4) in skeletal muscle, bone, and pituitary of castrated male rats. Twelve weeks after castration, animals were treated with S-4 (3 or 10 mg/kg), dihydrotestosterone (DHT) (3 mg/kg), or vehicle for 8 wk. S-4 (3 and 10 mg/kg) restored soleus muscle mass and strength and levator ani muscle mass to that seen in intact animals. Similar changes were also observed in DHT-treated (3 mg/kg) animals. Compared with the anabolic effects observed in muscle, DHT (3 mg/kg) stimulated prostate and seminal vesicle weights moire than 2-fold greater than that observed in intact controls, whereas S-4 (3 mg/kg) returned these androgenic organs to only 16 and 17%, respectively, of the control levels. S-4 (3 and 10 mg/kg) and DHT (3 mg/kg) restored castration-induced loss in lean body mass. Furthermore, S-4 treatment caused a significantly larger increase in total body bone mineral density than DHT. S-4 (3 and 10 mg/kg) also demonstrated agonist activity in the pituitary and significantly decreased plasma LH and FSH levels in castrated animals in a dose-dependent manner. In summary, the strong anabolic effects of S-4 in skeletal muscle, bone, and pituitary were achieved with minimal pharmacologic effect in the prostate. The tissue-selective pharmacologic activity of SARMs provides obvious advantages over steroidal androgen therapy and demonstrates the promising therapeutic utility that this new class of drugs may hold.
Christopher C Coss - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetic drug interactions of the selective androgen Receptor Modulator gtx 024 enobosarm with itraconazole rifampin probenecid celecoxib and rosuvastatin
Investigational New Drugs, 2016Co-Authors: Christopher C Coss, Amanda Jones, James T DaltonAbstract:GTx-024 (also known as enobosarm) is a first in class selective androgen Receptor Modulator being developed for diverse indications in oncology. Preclinical studies of GTx-024 supported the evaluation of several potential drug-drug interactions in a clinical setting. A series of open-label Phase I GTx-024 drug-drug interaction studies were designed to interrogate potential interactions with CYP3A4 inhibitor (itraconazole), a CYP3A4 inducer (rifampin), a pan-UGT inhibitor (probenecid), a CYP2C9 substrate (celecoxib) and a BCRP substrate (rosuvastatin). The plasma pharmacokinetics of GTx-024, its major metabolite (GTx-024 glucuronide), and each substrate were characterized in detail. Itraconazole administration had no effect on GTx-024 pharmacokinetics. Likewise, GTx-024 administration did not significantly change the pharmacokinetics of celecoxib or rosuvastatin. Rifampin administration had the largest impact on GTx-024 pharmacokinetics of any co-administered agent and reduced the maximal plasma concentration (Cmax) by 23 % and the area under the curve (AUC∞) by 43 %. Probenecid had a complex interaction with GTx-024 whereby both GTx-024 plasma levels and GTx-024 glucuronide plasma levels (AUC∞) were increased by co-administration of the UGT inhibitor (50 and 112 %, respectively). Overall, GTx-024 was well tolerated and poses very little risk of generating clinically relevant drug-drug interactions.
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selective androgen Receptor Modulator treatment improves muscle strength and body composition and prevents bone loss in orchidectomized rats
Endocrinology, 2005Co-Authors: Wenqing Gao, Christopher C Coss, Duane D Miller, Peter J Reiser, Mitch A Phelps, Jeffrey D Kearbey, James T DaltonAbstract:The partial agonist activity of a selective androgen Receptor Modulator (SARM) in the prostate was demonstrated in orchidectomized rats. In the current study, we characterized the full agonist activity of S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide (a structurally related SARM referred to in other publications and hereafter as S-4) in skeletal muscle, bone, and pituitary of castrated male rats. Twelve weeks after castration, animals were treated with S-4 (3 or 10 mg/kg), dihydrotestosterone (DHT) (3 mg/kg), or vehicle for 8 wk. S-4 (3 and 10 mg/kg) restored soleus muscle mass and strength and levator ani muscle mass to that seen in intact animals. Similar changes were also observed in DHT-treated (3 mg/kg) animals. Compared with the anabolic effects observed in muscle, DHT (3 mg/kg) stimulated prostate and seminal vesicle weights moire than 2-fold greater than that observed in intact controls, whereas S-4 (3 mg/kg) returned these androgenic organs to only 16 and 17%, respectively, of the control levels. S-4 (3 and 10 mg/kg) and DHT (3 mg/kg) restored castration-induced loss in lean body mass. Furthermore, S-4 treatment caused a significantly larger increase in total body bone mineral density than DHT. S-4 (3 and 10 mg/kg) also demonstrated agonist activity in the pituitary and significantly decreased plasma LH and FSH levels in castrated animals in a dose-dependent manner. In summary, the strong anabolic effects of S-4 in skeletal muscle, bone, and pituitary were achieved with minimal pharmacologic effect in the prostate. The tissue-selective pharmacologic activity of SARMs provides obvious advantages over steroidal androgen therapy and demonstrates the promising therapeutic utility that this new class of drugs may hold.
Kenji Chiba - One of the best experts on this subject based on the ideXlab platform.
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fingolimod fty720 sphingosine 1 phosphate Receptor Modulator shows superior efficacy as compared with interferon β in mouse experimental autoimmune encephalomyelitis
International Immunopharmacology, 2011Co-Authors: Kenji Chiba, Hirotoshi Kataoka, Kunio Sugahara, Kyoko Shimano, Mamoru Koyama, Atsushi Fukunari, Noriyasu Seki, Takahisa SugitaAbstract:Fingolimod (FTY720), a sphingosine 1-phosphate (S1P) Receptor Modulator, inhibits S1P-dependent lymphocyte egress from secondary lymphoid organs and is highly effective in experimental autoimmune encephalomyelitis (EAE) in mice. In this study, we directly compared the therapeutic effects of FTY720 and recombinant mouse interferon (rm-IFN)-β on relapse and progression of EAE in mice. When FTY720 at oral dose of 0.03 to 1 mg/kg was administered daily after establishment of EAE induced by myelin proteolipid protein (PLP) in SJL/J mice, relapse of EAE was significantly inhibited during administration period. Subcutaneous injection of rm-IFN-β (10,000 IU/mouse) also inhibited the relapse of EAE at early period; however EAE was relapsed in all the mice within administration period. Therapeutic administration of FTY720 (0.03 to 1 mg/kg) significantly improved the symptoms of chronic EAE induced by myelin oligodendrocyte glycoprotein in C57BL/6 mice whereas rm-IFN-β (10,000 IU/mouse) showed no clear effect. These results indicate that FTY720 is more efficacious in mouse EAE as compared with rm-IFN-β. FTY720 markedly reduced the frequency of PLP-specific Th17 and Th1 cells in the spinal cord of EAE mice. On the contrary, FTY720 increased the frequency of PLP-specific Th17 and Th1 cells in the inguinal lymph nodes, suggesting inhibition of egress of myelin antigen-specific Th cells from draining lymph nodes. From these results, the ameliorating effects of FTY720 on EAE are likely due to reduction of infiltration of myelin antigen-specific Th17 and Th1 cells into the central nervous system.
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fty720 sphingosine 1 phosphate Receptor Modulator ameliorates experimental autoimmune encephalomyelitis by inhibition of t cell infiltration
Cellular & Molecular Immunology, 2005Co-Authors: Hirotoshi Kataoka, Kunio Sugahara, Kyoko Shimano, Koji Teshima, Mamoru Koyama, Atsushi Fukunari, Kenji ChibaAbstract:FTY720, a sphingosine 1-phosphate Receptor Modulator, induces a marked decrease in the number of peripheral blood lymphocytes and exerts immunomodulating activity in various experimental allograft and autoimmune disease models. In this study, we evaluated the effect of FTY720 and its active metabolite, (S)-enantiomer of FTY720-phosphate [(S)-FTY720-P] on experimental autoimmune encephalomyelitis (EAE) in rats and mice. Prophylactic administration of FTY720 at 0.1 to 1 mg/kg almost completely prevented the development of EAE, and therapeutic treatment with FTY720 significantly inhibited the progression of EAE and EAE-associated histological change in the spinal cords of LEW rats induced by immunization with myelin basic protein. Consistent with rat EAE, the development of proteolipid protein-induced EAE in SJL/J mice was almost completely prevented and infiltration of CD4(+) T cells into spinal cord was decreased by prophylactic treatment with FTY720 and (S)-FTY720-P. When FTY720 or (S)-FTY720-P was given after establishment of EAE in SJL/J mice, the relapse of EAE was markedly inhibited as compared with interferon-beta, and the area of demyelination and the infiltration of CD4(+) T cells were decreased in spinal cords of EAE mice. Similar therapeutic effect by FTY720 was obtained in myelin oligodendrocyte glycoprotein-induced EAE in C57BL/6 mice. These results indicate that FTY720 exhibits not only a prophylactic but also a therapeutic effect on EAE in rats and mice, and that the effect of FTY720 on EAE appears to be due to a reduction of the infiltration of myelin antigen-specific CD4(+) T cells into the inflammation site.
Kristof Chwalisz - One of the best experts on this subject based on the ideXlab platform.
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Effects of the selective progesterone Receptor Modulator asoprisnil on uterine artery blood flow, ovarian activity, and clinical symptoms in patients with uterine leiomyomata scheduled for hysterectomy.
The Journal of Clinical Endocrinology & Metabolism, 2008Co-Authors: Julia Wilkens, Kristof Chwalisz, Iain T. Cameron, Cong Han, Jane Walker, Susan Ingamells, Alexandra C. Lawrence, Mary Ann Lumsden, Dharani K. Hapangama, Alistair R.w. WilliamsAbstract:Introduction: Asoprisnil, a novel orally active selective progesterone Receptor Modulator, is being studied for the management of symptomatic uterine leiomyomata. The exact mechanism of action is not yet discerned. The primary objectives of this double-blind, randomized, placebo-controlled study included evaluation of the effect of asoprisnil on uterine artery blood flow. Furthermore, we assessed effects of asoprisnil on leiomyoma symptoms. Patients and Methods: Thirty-three premenopausal patients scheduled for hysterectomy due to symptomatic uterine leiomyomata were recruited in four centers and treated with 10 or 25 mg asoprisnil or placebo for 12 wk before surgery. At baseline and before hysterectomy, all patients underwent sonographic assessment to measure impedance to uterine artery blood flow, determined by resistance index and pulsatility index, as well as volumes of largest leiomyoma and uterus. In addition, patients recorded intensity and frequency of menstrual bleeding on a menstrual pictogram. ...
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selective progesterone Receptor Modulator asoprisnil down regulates collagen synthesis in cultured human uterine leiomyoma cells through up regulating extracellular matrix metalloproteinase inducer
Human Reproduction, 2008Co-Authors: Akira Morikawa, Deborah A Demanno, Kristof Chwalisz, Noriyuki Ohara, Shigeki Yoshida, Koji Nakabayashi, Takeshi MaruoAbstract:BACKGROUND: A recent clinical trial demonstrated that selective progesterone Receptor Modulator asoprisnil is effective in reducing uterine leiomyoma volume. We investigated the effects of asoprisnil in vitro on the expression of the extracellular matrix (ECM)-remodeling enzymes and collagens in cultured leiomyoma and matching normal myometrial cells. METHODS: The expression of extracellular matrix metalloproteinase inducer (EMMPRIN), matrix metalloproteinases (MMPs), tissue inhibitors of MMP (TIMPs) and collagens were assessed by western blot analysis. RESULTS: Untreated cultured leiomyoma cells had significantly lower EMMPRIN ( P< 0.05), MMP-1 ( P< 0.05) and membrane type 1-MMP (MT1-MMP) ( P< 0.01) protein contents, but significantly higher TIMP-1 ( P< 0.05), TIMP-2 ( P< 0.01), type I ( P< 0.05) and type III ( P< 0.01) collagen protein contents compared with untreated cultured myometrial cells. Treatment with asoprisnil at concentrations � 10 27 M for 48 h significantly ( P< 0.05) increased EMMPRIN, MMP-1 and MT1-MMP protein contents, and decreased TIMP-1 ( P< 0.05), TIMP-2 ( P< 0.01), type I ( P< 0.01) and type III ( P< 0.05 at 10 27 M; P< 0.01 at 10 26 M) collagen protein contents in cultured leiomyoma cells compared with control cultures. However, asoprisnil treatment did not affect the protein contents of ECM-remodeling enzymes and collagens in cultured myometrial cells. CONCLUSIONS: These results suggest that asoprisnil may reduce collagen deposit in the ECM of cultured leiomyoma cells through decreasing collagen synthesis and enhancing the expression of EMMPRIN, MMPs and TIMPs without comparable effects on cultured myometrial cells.
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asoprisnil j867 a selective progesterone Receptor Modulator for gynecological therapy
Steroids, 2003Co-Authors: Deborah A Demanno, Gerd Schubert, Walter Elger, Ramesh Garg, Ronald Lee, Birgitt Schneider, Holger Hessstumpp, Kristof ChwaliszAbstract:Asoprisnil is a novel selective steroid Receptor Modulator that shows unique pharmacodynamic effects in animal models and humans. Asoprisnil, its major metabolite J912, and structurally related compounds represent a new class of progesterone Receptor (PR) ligands that exhibit partial agonist and antagonist activities in vivo. Asoprisnil demonstrates a high degree of Receptor and tissue selectivity, with high-binding affinity for PR, moderate affinity for glucocorticoid Receptor (GR), low affinity for androgen Receptor (AR), and no binding affinity for estrogen or mineralocorticoid Receptors. In the rabbit endometrium, both asoprisnil and J912 induce partial agonist and antagonist effects. Asoprisnil induces mucification of the guinea pig vagina and has pronounced anti-uterotrophic effects in normal and ovariectomized guinea pigs. Unlike antiprogestins, asoprisnil shows only marginal labor-inducing activity during mid-pregnancy and is completely ineffective in inducing preterm parturition in the guinea pig. Asoprisnil exhibits only marginal antiglucocorticoid activity in transactivation in vitro assays and animal models. In male rats, asoprisnil showed weak androgenic and anti-androgenic properties. In toxicological studies in female cynomolgus monkeys, asoprisnil treatment abolished menstrual cyclicity and endometrial atrophy. Early clinical studies of asoprisnil in normal volunteers demonstrated a dose-dependent suppression of menstruation irrespective of the effects on ovulation, with no change in basal estrogen concentrations and no antiglucocorticoid effects. Unlike progestins, asoprisnil does not induce breakthrough bleeding. With favorable safety and tolerability profiles thus far, asoprisnil appears promising as a novel treatment of gynecological disorders, such as uterine fibroids and endometriosis.
Takeshi Maruo - One of the best experts on this subject based on the ideXlab platform.
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selective progesterone Receptor Modulator asoprisnil down regulates collagen synthesis in cultured human uterine leiomyoma cells through up regulating extracellular matrix metalloproteinase inducer
Human Reproduction, 2008Co-Authors: Akira Morikawa, Deborah A Demanno, Kristof Chwalisz, Noriyuki Ohara, Shigeki Yoshida, Koji Nakabayashi, Takeshi MaruoAbstract:BACKGROUND: A recent clinical trial demonstrated that selective progesterone Receptor Modulator asoprisnil is effective in reducing uterine leiomyoma volume. We investigated the effects of asoprisnil in vitro on the expression of the extracellular matrix (ECM)-remodeling enzymes and collagens in cultured leiomyoma and matching normal myometrial cells. METHODS: The expression of extracellular matrix metalloproteinase inducer (EMMPRIN), matrix metalloproteinases (MMPs), tissue inhibitors of MMP (TIMPs) and collagens were assessed by western blot analysis. RESULTS: Untreated cultured leiomyoma cells had significantly lower EMMPRIN ( P< 0.05), MMP-1 ( P< 0.05) and membrane type 1-MMP (MT1-MMP) ( P< 0.01) protein contents, but significantly higher TIMP-1 ( P< 0.05), TIMP-2 ( P< 0.01), type I ( P< 0.05) and type III ( P< 0.01) collagen protein contents compared with untreated cultured myometrial cells. Treatment with asoprisnil at concentrations � 10 27 M for 48 h significantly ( P< 0.05) increased EMMPRIN, MMP-1 and MT1-MMP protein contents, and decreased TIMP-1 ( P< 0.05), TIMP-2 ( P< 0.01), type I ( P< 0.01) and type III ( P< 0.05 at 10 27 M; P< 0.01 at 10 26 M) collagen protein contents in cultured leiomyoma cells compared with control cultures. However, asoprisnil treatment did not affect the protein contents of ECM-remodeling enzymes and collagens in cultured myometrial cells. CONCLUSIONS: These results suggest that asoprisnil may reduce collagen deposit in the ECM of cultured leiomyoma cells through decreasing collagen synthesis and enhancing the expression of EMMPRIN, MMPs and TIMPs without comparable effects on cultured myometrial cells.
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progesterone Receptor Modulator cdb 2914 induces extracellular matrix metalloproteinase inducer in cultured human uterine leiomyoma cells
Molecular Human Reproduction, 2008Co-Authors: Noriyuki Ohara, Jin Liu, Mariko Amano, Regine Sitrukware, Shigeki Yoshida, Takeshi MaruoAbstract:Effects of progesterone Receptor Modulator CDB-2914 on the expression of the extracellular matrix (ECM) components were examined in cultured human uterine leiomyoma and myometrial cells. ECM metalloproteinase inducer (EMMPRIN), matrix metalloproteinases (MMPs), tissue inhibitors of MMP (TIMPs) and collagen levels were assessed by Western blot analysis, MMP activity assay and real-time RT – PCR. RNA interference (RNAi) of EMMPRIN was performed using small interfering mRNA. In cultured leiomyoma cells, CDB-2914 treatment at concentrations greater than or equal to 10 28 M significantly increased EMMPRIN, MMP-1 and MMP-8 protein contents and MMP-1, MMP-2, MMP-3 and MMP-9 mRNA levels, and activity of MMP-1, MMP-2, MMP-3 and MMP-9 in the medium. TIMP-1 and TIMP-2 were significantly decreased at mRNA and protein levels by CDB-2914 treatment at concentrations � 10 27 M in these cells. CDB-2914 treatment decreased types I and III collagen protein contents. However, CDB-2914 treatment did not affect the ECM component expression in cultured myometrial cells. RNAi of EMMPRIN abrogated CDB-2914-mediated both induction of MMPs and reduction of TIMPs and collagens in cultured leiomyoma cells. These results suggest that CDB-2914 modulates the expression of EMMPRIN, MMPs, TIMPs and collagens in cultured leiomyoma cells without comparable effects on myometrial cells.
