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Endometriosis is an estrogen (ER)-dependent gynecological disease caused by the growth of endometrial tissue at extrauterine sites. Current endocrine therapies address the estrogenic aspect of disease and offer some relief from pain but are associated with significant side effects. Immune dysfunction is also widely believed to be an underlying contributor to the pathogenesis of this disease. This study evaluated an inhibitor of c-Jun N-terminal kinase, bentamapimod (AS602801), which interrupts immune pathways, in 2 rodent endometriosis models. Treatment of nude mice bearing xenografts biopsied from women with endometriosis (BWE) with 30 mg/kg AS602801 caused 29% regression of lesion. Medroxyprogesterone acetate (MPA) or progesterone (PR) alone did not cause regression of BWE lesions, but combining 10 mg/kg AS602801 with MPA caused 38% lesion regression. In human endometrial organ cultures (from healthy women), treatment with AS602801 or MPA reduced matrix metalloproteinase-3 (MMP-3) release into culture medium. In organ cultures established with BWE, PR or MPA failed to inhibit MMP-3 secretion, whereas AS602801 alone or MPA + AS602801 suppressed MMP-3 production. In an autologous rat endometriosis model, AS602801 caused 48% regression of lesions compared to GnRH antagonist Antide (84%). AS602801 reduced inflammatory cytokines in endometriotic lesions, while levels of cytokines in ipsilateral horns were unaffected. Furthermore, AS602801 enhanced natural killer cell activity, without apparent negative effects on uterus. These results indicate that bentamapimod induced regression of endometriotic lesions in endometriosis rodent animal models without suppressing ER action. c-Jun N-terminal kinase inhibition mediated a comprehensive reduction in cytokine secretion and moreover was able to overcome PR resistance. [ABSTRACT FROM AUTHOR]

Objective:To determine the level of expression of selected matrix metalloproteinases in uterine leiomyoma compared with unaffected myometrium in an effort to explain the abnormal accumulation of extracellular matrix in the leiomyoma.Methods:The levels of matrix metalloproteinase (MMP) mRNA in leiomyoma and myometrium weer measured in samples from 22 patients during either proliferative (n = 6) or secretory phases (n = 16) of the menstrual cycle. Relative amounts of collagenase (MMP-1) and stromelysin (MMP-3) mRNAs were measured by Northern blot analysis, and amounts of stromelysin 3 (MMP-11) and matrilysin (MMP-7) mRNA from each sample were determined by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and normalized to β-actin mRNA.Results:The levels of MMP-1 and MMP-3 mRNAs were similar in both leiomyoma and unaffected myometrium. The levels of MMP-11 mRNA were twofold greater in leiomyoma compared with myometrium throughout the menstrual cycle, and the differences in the levels of MMP-11 were significantly different during the secretory phase. The level of MMP-7 mRNA expression was similar in leiomyoma, myometrium, and endometrium.Conclusions:Among the metalloproteinases examined in this study, only the levels of MMP-11 mRNA were elevated in leiomyoma compared with myometrium. The increased expression of MMP-11 in uterine leiomyoma compared with myometrium is analagous to previously reported elevations of MMP-11 mRNA in dermatofibromas compared with unaffected skin. The increased expression of MMP-11 mRNA in fibroid tumors suggests that this MMP may be involved in the formation of a more fibrous extracellular matrix in leiomyoma relative to unaffected myometrium. [ABSTRACT FROM PUBLISHER]