MECHANISM OF PROSTATE CANCER GROWTH INHIBITION BY TAMOXIFEN

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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.