Riva C, Barra Y, Carcassonne Y, Cano J P, Rustum Y
INSERM U 278, Faculté de Pharmacie, Marseille, France.
Chemotherapy. 1992;38(5):358-66. doi: 10.1159/000239026.
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.
胞苷脱氨酶对阿糖胞苷（ara-C）的脱氨作用是该药物失活的主要方式，这可能导致对ara-C产生耐药性。本研究旨在确定四氢尿苷（THU；一种有效的胞苷脱氨酶抑制剂）对ara-C在人细胞中的转运和代谢的影响。在存在50微克/毫升THU的情况下，观察到ara-C快速转运到新鲜分离的肝细胞中，并且未改变的药物在细胞内的积累增加。THU抑制ara-C在细胞内的脱氨作用达80%，并减缓该化合物在细胞外的消除。用1微克/毫升ara-C加50微克/毫升THU孵育后达到的细胞内ara-C浓度与单独使用ara-C（10微克/毫升）时达到的浓度相似。用THU（50微克/毫升）和ara-C（1微克/毫升）联合处理白血病K562细胞导致细胞内阿糖胞苷三磷酸的形成增加高达两倍。
