Development of new therapeutic modalities based on the analysis of the pathogenesis and biological features of leiomyoma

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Regarding the proliferation of uterine leiomyoma, the posttranscriptional modification of Ref-1 was revealed to associate with the proliferation of leiomyoma cells in vivo and in vitro. Mast cells in the uterus were suggested to enhance the proliferation of smooth muscle cells. Apoptosis-resistant character of leiomyoma cells was suggested through the studies of sFRP1 (a modulator of Wnt signaling), S100A11 (S100 protein family), and PEP-19. In addition, Ref-1, S100A11, and β catenin were suggested to be involved in the pathophysiology of leiomyosarcoma.Regarding the pathogenesis of leiomyoma, we hypothesize that leiomyomas resale from proliferation of smooth muscle cells is the myometrial tissue that survives the repeated ischemic-reperfusion stress experienced during the menstrual cycle. The blood supply to the myometrium in vivo is knows to decrease daring uterine contraction, particularly daring menstruation. In each luteal phase of the menstrual cycle, myometrial smooth muscles ex … More hibit proliferative activity, in preparation for pregnancy. However, if pregnancy does not occur, the proliferative activity of the myometrial smooth muscle colts may be interrupted at the time of menstruation. Myometrial contraction, winch results in the cessation of menstrual blinding, probably induces an ischemic / hypoxic state in the myometrial smooth muscle cells. Ischemic injury could occur in these cells which are in the proliferative phase. It is suggested that them injured colts could become candidates for progenitor cells of leiomyomas. Somatic mutation could well be induced in these cells after surviving many repeats of the menstrual cycle. In this respect, immunohistochemically we found e few p53- or p21-positive cells in the myometrium exclusively in the follicular phase of the menstrual cycle. This highly suggests that there exists smooth muscle cells that were injured their DNA during the menses, and these cells would be repaired during the cell-cycle arrest or eliminated through apoptosis. If the cells with injured DNA may acquire apoptosis-resistance expressing molecules such as sFRP1 and S100A11, these cells become the candidates of the precursor of leiomyoma cell.Regarding the treatment, tranilast that suppresses fibrosis or arts as a mast cell stabilizer, became a candidate of a new therapeutic agent. Tranilast inhibited the proliferation of cultured leiomyoma cells in a dose-dependent manner without any cytotoxic effort. We also demonstrated that uterine arterial embolization successfully reduced the uterine size of diffuse leiomyomatosis, suggesting that this procedure may be a premising new therapeutic modality for this intractable disease without loss of fertility. Less