Laliberté J, Marquez V E, Momparler R L
Département de Pharmacologie, Université de Montréal, Québec, Canada.
Cancer Chemother Pharmacol. 1992;30(1):7-11. doi: 10.1007/BF00686478.
Deamination of the nucleoside analogues ARA-C and 5-AZA-CdR by CR deaminase results in a loss of antileukemic activity. To prevent the inactivation of these analogues, inhibitors of CR deaminase may prove to be useful agents. In the present study we investigated the effects of the deaminase inhibitors Zebularine, 5-F-Zebularine, and diazepinone riboside on the deamination of CR, ARA-C, and 5-AZA-CdR using highly purified human CR deaminase (EC 3.5.4.5). These inhibitors produced a competitive type of inhibition with each substrate, the potency of which followed the patterns diazepinone riboside greater than 5-F-Zebularine and THU greater than Zebularine. 5-AZA-CdR was more sensitive than ARA-C to the inhibition produced by these deaminase inhibitors. The inhibition constants for diazepinone riboside lay in the range of 5-15 nM, suggesting that this inhibitor could be an excellent candidate for use in combination chemotherapy with either ARA-C or 5-AZA-CdR in patients with leukemia.
胞嘧啶脱氨酶对核苷类似物阿糖胞苷（ARA-C）和5-氮杂胞苷（5-AZA-CdR）的脱氨作用会导致抗白血病活性丧失。为防止这些类似物失活，胞嘧啶脱氨酶抑制剂可能是有用的药物。在本研究中，我们使用高度纯化的人胞嘧啶脱氨酶（EC 3.5.4.5）研究了脱氨酶抑制剂泽布勒林、5-氟-泽布勒林和二氮杂环己酮核糖苷对胞嘧啶（CR）、阿糖胞苷和5-氮杂胞苷脱氨作用的影响。这些抑制剂对每种底物产生竞争性抑制，其效力遵循二氮杂环己酮核糖苷大于5-氟-泽布勒林以及噻唑烷二酮大于泽布勒林的模式。5-氮杂胞苷比阿糖胞苷对这些脱氨酶抑制剂产生的抑制更敏感。二氮杂环己酮核糖苷的抑制常数在5 - 15 nM范围内，表明该抑制剂可能是白血病患者与阿糖胞苷或5-氮杂胞苷联合化疗的优秀候选药物。
