title: In vitro antitumor effect of hydroxyurea on hormone-refractory prostate cancer cells and its potentiation by phenylbutyrate.
abstract: Previous clinical trials have suggested that hydroxyurea may possess some activity against prostate cancer. The in vitro antiproliferative activity of hydroxyurea was evaluated in three hormone-refractory prostate cancer cell lines, PC-3, DU-145 and PC-3M. Fifty-percent inhibition of growth in all three cell lines required prolonged (120 h) exposure to hydroxyurea at a concentration of approximately 100 microM. Using pharmacokinetic data obtained during the course of a clinical trial of hydroxyurea, we simulated a dosing regimen that would sustain plasma drug concentrations above 100 microM 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 regimen is likely to generate an unacceptable degree of myelosuppression, in vitro combination studies were conducted with hydroxyurea and phenylbutyrate, a new differentiating agent with no myelosuppressive effects. These studies resulted in a reduction of the hydroxyurea concentration necessary for 50% growth inhibition (50 microM of hydroxyurea plus 0.5 mM of phenylbutyrate). A regimen designed to achieve that hydroxyurea 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 prostate cancer.
authors.affiliation: Clinical Pharmacology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: W D
authors.initials: WD
authors.lastname: Figg
authors.forename: R G
authors.initials: RG
authors.lastname: Walls
authors.forename: M R
authors.initials: MR
authors.lastname: Cooper
authors.forename: A
authors.initials: A
authors.lastname: Thibault
authors.forename: O
authors.initials: O
authors.lastname: Sartor
authors.forename: N A
authors.initials: NA
authors.lastname: McCall
authors.forename: C E
authors.initials: CE
authors.lastname: Myers
authors.forename: D
authors.initials: D
authors.lastname: Samid
mesh_terms: D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D006728:Hormones / Q000494:pharmacology*; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008954:Models, Biological; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000473:pathology; D010654:Phenylbutyrates / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D006728:Hormones; D010654:Phenylbutyrates; D006918:Hydroxyurea