Uterine leiomyomas are the most common gynecological tumor in women and have a significant effect on women's health. Little is known about the etiology of uterine leiomyoma and currently there is no satisfactory therapy for these tumors. We have recently described an animal model for this disease in which spontaneous uterine leiomyomas arise at a high frequency. Cell lines from these tumors have been established and characterized making this a unique in vitro/in vivo animal model for developing therapeutic approaches for leiomyoma. In preliminary studies, we determined that the steroid hormone antagonist tamoxifen (TAM) could inhibit the growth of these cells in vitro and in a nude mouse xenograft assay. Furthermore, it was noted that the ability of this drug to inhibit cell growth correlated with the production of IGF-I by tumor cells that expressed receptors for this growth factor, suggesting that TAM was acting via interruption of an IGF-I autocrine loop. Our long-range goal is to determine the efficacy of steroid hormone antagonists for treatment of uterine leiomyoma. As a first step toward accomplishing this goal, we will investigate the mechanism by which TAM inhibits uterine leiomyoma growth in our rat model.
SPECIFIC AIMS of the proposed experiments are: 1) Test the hypothesis that IGF-I is an autocrine growth factor for leiomyomas 2) Test the hypothesis that TAM interrupts this autocrine loop 3) Determine whether induction of apoptosis is the mechanism by which TAM inhibits the growth of these cells and 4) Evaluate the ability of TAM to modulate leiomyoma growth in situ. Data generated from these studies will allow us to target this IGF-I autocrine loop and use induction of apoptosis as a biomarker of efficacy to develop new hormonal therapies for treatment of this important gynecologic neoplasm.
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