Effect of tetrahydrouridine on metabolism and transport of 1-beta-D-arabinofuranosylcytosine in human cells.
Deamination of cytosine arabinoside (ara-C) by cytidine deaminase is the main mode of inactivation of this drug which can be responsible for ara-C resistance. The present study was undertaken to determine the effect of tetrahydrouridine (THU; a potent inhibitor of cytidine deaminase) on ara-C transport and metabolism in human cells. A rapid transport of ara-C into freshly isolated hepatocytes and an increased intracellular accumulation of the unchanged drug were observed in the presence of 50 micrograms/ml THU. THU inhibited the intracellular deamination of ara-C by 80% and slowed elimination of the compound extracellularly. The intracellular ara-C concentrations achieved after incubation with 1 micrograms/ml ara-C plus 50 micrograms/ml THU are similar to those attained with ara-C (10 micrograms/ml) alone. Treatment of leukemic K562 cells with the combination of THU (50 micrograms/ml) and ara-C (1 micrograms/ml) led to an augmentation of intracellular ara-C triphosphate formation up to twofold.
Riva
C
C
INSERM U 278, Faculté de Pharmacie, Marseille, France.
Barra
Y
Y
Carcassonne
Y
Y
Cano
J P
JP
Rustum
Y
Y
D002478:Cells, Cultured; D003561:Cytarabine / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D007942:Leukemia, Experimental / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D009700:Nucleoside Deaminases / Q000378:metabolism; D013767:Tetrahydrouridine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D003561:Cytarabine; D013767:Tetrahydrouridine; D009700:Nucleoside Deaminases