MECHANISM OF PROSTATE CANCER GROWTH INHIBITION BY TAMOXIFEN

他莫昔芬抑制前列腺癌生长的机制

• 批准号: 2464561
• 负责人: R BERGAN
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2464561
• 关键词: clinical research; guanine nucleotide binding protein; human subject; human therapy evaluation; neoplasm /cancer chemotherapy; prostate neoplasms; tamoxifen; transforming growth factors

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.

他莫昔芬已被广泛用于治疗乳腺癌。在