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 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.
Figg
W D
WD
Clinical Pharmacology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Walls
R G
RG
Cooper
M R
MR
Thibault
A
A
Sartor
O
O
McCall
N A
NA
Myers
C E
CE
Samid
D
D
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
D006728:Hormones; D010654:Phenylbutyrates; D006918:Hydroxyurea