GROWTH INHIBITORY EFFECT OF GOSSYPOL ON CANINE/HUMAN BPH

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Human benign prostatic hyperplasia (hBPH) is one of the most important diseases in men of advancing age, its etiology is not clearly defined. Undoubtedly, the onset and progression of hBPH is regulated by multiple endocrine factors. Thus, increasing our understanding of hBPH demands a multidisciplinary approach involving both basic and clinical research. We will attempt to achieve this goal by utilizing such an approach, in which basic and clinical research of an appropriate canine model will provide for the development of novel therapeutic approaches for hBPH patients. The rationale for our proposal is based on the following hypotheses and evidence: 1) testicular androgens are not the sole limiting factor for regulation of the growth of normal and hyperplastic prostates in both cBPH and hBPH; 2) cellular interactions between the prostatic stromal and epithelial components play vital roles in the onset and regression of prostatic hyperplasia in both cBPH and hBPH; 3) resistance of prostatic stromal cells to treatment is much higher than that of epithelial cells; 4) deprivation of androgen by castration in cBPH will not completely suppress the growth and function of prostate stromal components; 5) GP possesses growth inhibitory and antisteroidogenic effects on prostate tissues in different species including humans and that GP is capable of reducing steroids thereby causing disruptive effects in both epithelial and stromal components of GP-treated animals. These drastic, GP-induced changes in the stromal cells have important clinical implications for developing new therapeutic strategies for cBPH and hBPH patients; and 6) evidence of high specific binding of GP in subcellular organelles of prostatic tissues and identification of new prostatic proteins whose expressions are regulated by GP and testosterone. The specific aims of our proposed study are: 1) to use in vivo and in vitro models to examine the regulation of prostate growth in experimentally induced cBPH; 2) to use in vitro models to investigate differential functions of epithelial and stromal cells prepared from specimens surgically removed from different regions of hBPH; 3) to evaluate the regulation of prostate regression in spontaneous cBPH patients after castration and GP treatment; and 4) to formulate new therapeutic strategies for clinical trails in hBPH patients based on experimental data generated from the basic research accomplished by aims 1, 2 and 3. This grant application combines our investigators' expertise in reproductive endocrinology, steroid biochemistry, cellular biology and clinical medicine in evaluating GP as a potential alternative agent for treatment of BPH.