MECHANISM OF PROSTATE CANCER GROWTH INHIBITION BY TAMOXIFEN

“我们之前已经证明， 他莫昔芬抑制前列腺癌（PCa）细胞生长， IC 50在低微摩尔范围内。虽然这些浓度 一个对数高于血清中获得的常规 治疗，他们可以达到高剂量他莫昔芬治疗。 以前我们也证明了他莫昔芬增加了 PCa细胞对TGF-β 1生长抑制的敏感性， 与细胞周期抑制蛋白的诱导有关， p21 cip 1/waf 1和G1/S期细胞阻滞。最近 研究表明，他莫昔芬对PKC的抑制作用可能 代表了一个重要的主要作用部位， 抑制作用他莫昔芬抑制体内PKC活性5小时后， 处理，在12小时诱导p21 cip 1/waf 1， Rb的去磷酸化24小时。PKC抑制剂 Ro 31 -8220是一种已知的PKC抑制剂，也可诱导p21 cip 1/waf 1 并抑制PCa细胞的生长。虽然PKC与 这些研究，相关调查表明， 抑制作用不是通过雌激素、钙通道介导的 阻断、抗雌激素结合位点或环AMP 磷酸二酯酶介导的活性（与他莫昔芬一样重要 会有这样的效果）。因此，这些研究表明， 浓度的他莫昔芬作为一个重要的增长作用 PCa中的调节位点。高剂量的II期临床试验 开始使用他莫昔芬来测试人体内的功效， 最近完成的。在该试验中观察到临床活性。 利用该试验的临床样本，目前正在进行研究， 确定体内是否发生类似的影响。这些研究 重要的是，它们表明， PCa，即对TGF-β 1反应性的丧失，可以逆转。和 针对这种疾病的治疗似乎与临床 功效基于最佳治疗将 需要采取多模式办法时，进行了研究， 确定生物疗法的疗效（即增加 PCa细胞对TGF-β 1的敏感性 可用的细胞毒性治疗。这些调查表明， 在高浓度的 他莫昔芬和长春碱。一项I/II期临床试验已经 开始测试临床疗效。"

"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."