MECHANISM OF PROSTATE CANCER GROWTH INHIBITION BY TAMOXIFEN

三苯氧胺已被广泛用于治疗乳腺癌。在 这种能力，其雌激素拮抗剂的性质代表了一个重要的 体内机制 药理学作用，但与 然而，雌激素途径与他莫昔芬有关。 这些 结果表明其对前列腺癌（PCa）具有治疗潜力。 这项研究试图确定他莫昔芬是否有任何活性， PCa，如果50，通过什么机制。 我们证明了他莫昔芬可以抑制PCa细胞的生长， IC 50值范围为5.5-10 μ M。 而常规给药血清 高剂量他莫昔芬的浓度仅为0.5 μ M， 可以容易地获得超过10 μ M的治疗浓度。 我们 研究表明，他莫昔芬对PCa细胞的生长抑制是 不依赖于功能性雌激素途径，而雌激素 不改变生长抑制作用。 我们证明了他莫昔芬 增加PCa细胞对生长抑制作用的敏感性 转化生长因子-β（TGF-β）。 他莫昔芬治疗 不增加TGF-β分泌。 然而，它确实直接导致了 通常与TGF-β作用相关的作用，即诱导 a G1/S期细胞周期阻滞，并诱导细胞周期调节 蛋白质，p21。 基于这些，2期临床试验的早期结果 研究表明，高剂量他莫昔芬治疗具有活性， 激素难治性前列腺癌的患者。

Tamoxifen has been used widely for the treatment of breast cancer. In this capacity, its estrogen antagonist properties represent an important in vivo mechanism. Pharmacologic effects other than those related to the estrogen pathway have been associated with tamoxifen, however. These effects suggested therapeutic potential against prostate cancer (PCa). This study sought to determine whether tamoxifen had any activity against PCa, and if 50, by what mechanism. We demonstrated that tamoxifen could inhibit the growth of PCa cells with 1C50 values ranging from 5.5-10 microM. While conventional dosing serum concentrations of only 0.5 microM are attained, with high dose tamoxifen therapy concentrations exceeding 10 microM can easily be attained. Our studies demonstrated that growth inhibition of PCa cells by tamoxifen was not dependent upon a functional estrogen pathway, and that estrogens did not alter growth inhibitory effects. We demonstrate that tamoxifen increased the sensitivity of PCa cells to the growth inhibitory effects of transforming growth factor-beta (TGF-beta). Tamoxifen treatment did not increase TGF-beta secretion. It did, however, directly induce effects typically associated with TGF-beta action, namely induction of a G1/S phase cell cycle block, and induction of the cell cycle regulatory protein, p21. Early results from a phase 2 clinical trial, based upon these investigations, indicate that high dose tamoxifen therapy has activity in patients with hormone refractory prostate cancer.