""""""""DISCONTINUED We have previously shown that tamoxifen inhibits the growth of prostate cancer (PCa) cells with IC50s in the low micromolar range. While these concentrations are one log higher than that attained in the serum with conventional therapy, they can be attained with high dose tamoxifen therapy. Previously we also demonstrated that tamoxifen increases the sensitivity of PCa cells to growth inhibition by TGF-/, and that this is associated with induction of the cell cycle inhibitory protein, p21cip1/waf1, and G1/S phase cell cycle arrest. More recent investigations indicate that PKC inhibition by tamoxifen may represent an important primary site of action with respect to growth inhibition. Tamoxifen inhibits PKC activity in vivo 5 hours after treatment, induces p21cip1/waf1 at 12 hours, and causes dephosphorylation of Rb by 24 hours. Inhibition of PKC by Ro31-8220, a known inhibitor of PKC, also induces p21cip1/waf1 and inhibits the growth of PCa cells. While PKC was implicated in these studies, related investigations demonstrated that growth inhibition was not mediated through estrogenic, calcium channel blocking, antiestrogenic binding site, or cyclic AMP phosphodiesterase mediated activity (of importance as tamoxifen can have such effects). These studies, therefore, identify high concentrations of tamoxifen as acting at an important growth regulatory site in PCa. A phase II clinical trial of high dose tamoxifen was initiated to test in vivo efficacy in humans, and was recently completed. Clinical activity was observed in that trial. Utilizing clinical samples from that trial, studies are now ongoing to determine if similar effects are occurring in vivo. These studies are important as they demonstrate that an early phenotypic change in PCa, namely loss to TGF-/ responsiveness, can be reversed. And that therapy directed at such appears to be associated with clinical efficacy. Based upon the hypothesis that optimal therapy will require a multimodality approach, studies were undertaken to determine the efficacy of biologic therapy (i.e. increasing the sensitivity of PCa cells to TGF-/) in combination with the best available cytotoxic therapy. These investigations demonstrated that there was synergistic activity between high concentrations of tamoxifen and vinblastine. A phase I/II clinical trial has been initiated to test clinical efficacy.""""""""
