Effect of Tetrahydrouridine on Metabolism and Transport of 1-β-D-Arabinofuranosylcytosine in Human Cells

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Abstract
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 μg/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 μg/ml ara-C plus 50 μg/ml THU are similar to those attained with ara-C (10 μg/ml) alone. Treatment of leukemic K562 cells with the combination of THU (50 μg/ml) and ara-C (1 μg/ml) led to an augmentation of intracellular ara-C triphosphate formation up to twofold.

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