It is proposed in this revised renewal application that the regulation of growth and differentiation of prostatic carcinoma cells is related not only to receptor number but to the ability of the cells to metabolize 1a,25(OH)2D3. Studies are outlined to extend these observations by 1) further characterizing the mechanisms through which 1a,25(OH)2D3 regulates the expression of genes such as 24-hydroxylase prostate-specific antigen and early response genes such as c-jun and c- fos, 2) examining the interactions of 1a,25(OH)2D3 with 24 hydroxylase inhibitors and chemotherapeutic agents such as cisplatin and androgen receptor antagonists, and 3) moving the studies to an in vivo setting using nude mouse xenografts of human carcinoma cells. The role of VDr will be directly assessed using antisense constructs transfected into cell lines. Effects on growth will be monitored using both proliferation markers as well as assessing apoptotic cell death. Differentiation will be assessed by measuring the expression of PSA, prostate-specific acid phosphatase and/or 24 hydroxylase. It is the ultimate goal of this proposal to lay the foundation for clinically relevant studies on the use of vitamin D3 metabolites or analogues in the treatment of hormone refractory prostatic cancer or in the prevention of this increasingly common disease.
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