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

被引:13
作者
FIGG, WD
WALLS, RG
COOPER, MR
THIBAULT, A
SARTOR, O
MCCALL, NA
MYERS, CE
SAMID, D
机构
[1] Clinical Pharmacology Branch, National Cancer Institute, National Institutes of Health, Bethesda
关键词
HYDROXYUREA; PHENYLBUTYRATE; PROSTATE CANCER;
D O I
10.1097/00001813-199406000-00012
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 muM. 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 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 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 muM 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.
引用
收藏
页码:336 / 342
页数:7
相关论文
共 28 条
[1]  
ADAMSON RH, 1965, J PHARMACOL EXP THER, V150, P322
[2]  
ARIEL IM, 1970, CANCER-AM CANCER SOC, V25, P705, DOI 10.1002/1097-0142(197003)25:3<705::AID-CNCR2820250331>3.0.CO
[3]  
2-D
[4]  
BECKLOFF GERALD L., 1965, CANCER CHEMO THERAP REP, V48, P57
[5]  
BECKLOFF GL, 1976, INVEST UROL, V6, P530
[6]  
BELT RJ, 1980, CANCER, V46, P455, DOI 10.1002/1097-0142(19800801)46:3<455::AID-CNCR2820460306>3.0.CO
[7]  
2-N
[8]  
BLOEDOW CE, 1964, CANCER CHEMOTH REP, P39
[9]  
BOLTON B. H., 1965, CANCER CHEMOTHERAP REP, V46, P1
[10]  
BRUSILOW SW, 1987, METABOLIC BASIS INHE, P629