IN-VITRO ANTITUMOR EFFECT OF HYDROXYUREA ON HORMONE-REFRACTORY PROSTATE-CANCER CELLS AND ITS POTENTIATION BY PHENYLBUTYRATE

Previous clinical trials have suggested that hydroxyurea may possess s ome activity against prostate cancer. The in vitro antiproliferative a ctivity of hydroxyurea was evaluated in three hormone-refractory prost ate cancer cell lines, PC-3, DU-145 and PC-3M. Fifty-percent inhibitio n of growth in all three cell lines required prolonged (120 h) exposur e to hydroxyurea at a concentration of approximately 100 muM. Using ph armacokinetic data obtained during the course of a clinical trial of h ydroxyurea, we simulated a dosing regimen that would sustain plasma dr ug concentrations above 100 muM for 120 h (1 g loading dose, followed by 500 mg every 6 h for 5 days in a 70 kg man). Since this dosing regi men is likely to generate an unacceptable degree of myelosuppression, in vitro combination studies were conducted with hydroxyurea and pheny lbutyrate, a new differentiating agent with no myelosuppressive effect s. These studies resulted in a reduction of the hydroxyurea concentrat ion necessary for 50% growth inhibition (50 muM of hydroxyurea plus 0. 5 mM of phenylbutyrate). A regimen designed to achieve that hydroxyure a concentration (400 mg loading dose, followed by 200 mg every 6 h for 5 days) should be clinically achievable. Based on these results, this combination deserves further evaluation in patients with stage D pros tate cancer.