Akman S A, Ross D D, Joneckis C C, Fox B M, Bachur N R
Cancer Treat Rep. 1985 Jul-Aug;69(7-8):851-7.
We studied the effect of deoxyguanosine (dGuo) on cellular cytarabine (ara-C) nucleotide accumulation of the human leukemia cell line K562 and of bone marrow blast cells derived from patients with acute nonlymphocytic leukemia. Exposure of cells in culture to dGuo increased ara-C nucleotide accumulation measured in cell lysate, with an average increase of 386% (range, 242%-537%) of control in the presence of 500 microM dGuo. Maximal elevation occurred after 8 hours of exposure and remained constant through 48 hours. dGuo also enhanced deoxycytidine nucleotide accumulation, but dGuo enhancement favored accumulation of ara-C nucleotides over dCyd nucleotides. In cell cycle kinetic studies using flow cytometry, dGuo slowed accumulation of cells with apparent S-phase DNA content in a concentration-dependent fashion. However, neither the rate nor the magnitude of this effect correlated with the increase in ara-C nucleotide accumulation. Since the increase in ara-C nucleotide accumulation caused by dGuo could be prevented by 5 micrograms/ml of cycloheximide, this process appears to require new protein synthesis. Although these data suggest that the elevation of ara-C nucleotide accumulation caused by dGuo may represent induction of enzyme synthesis, other possibilities are discussed. Exposure of bone marrow blast cells obtained from patients with acute nonlymphocytic leukemia to dGuo for 16 hours in liquid culture also increased ara-C nucleotide accumulation. In six of seven studies, exposure to dGuo in concentrations from 50 to 500 microM increased ara-C nucleotide accumulation from 160% to 3400%. These data suggest that dGuo may alter ara-C metabolism in a clinically useful fashion.
我们研究了脱氧鸟苷（dGuo）对人白血病细胞系K562以及急性非淋巴细胞白血病患者来源的骨髓原始细胞中阿糖胞苷（ara-C）核苷酸积累的影响。在培养中，细胞暴露于dGuo会增加细胞裂解物中测得的ara-C核苷酸积累，在存在500 microM dGuo的情况下，平均比对照增加386%（范围为242%-537%）。最大升高在暴露8小时后出现，并在48小时内保持恒定。dGuo还增强了脱氧胞苷核苷酸的积累，但dGuo的增强作用更有利于ara-C核苷酸而非脱氧胞苷（dCyd）核苷酸的积累。在使用流式细胞术的细胞周期动力学研究中，dGuo以浓度依赖性方式减缓了具有明显S期DNA含量的细胞的积累。然而，这种作用的速率和幅度均与ara-C核苷酸积累的增加无关。由于5微克/毫升的环己酰亚胺可阻止dGuo引起的ara-C核苷酸积累增加，因此该过程似乎需要新的蛋白质合成。尽管这些数据表明dGuo引起的ara-C核苷酸积累增加可能代表酶合成的诱导，但也讨论了其他可能性。在液体培养中将急性非淋巴细胞白血病患者获得的骨髓原始细胞暴露于dGuo 16小时也增加了ara-C核苷酸积累。在七项研究中的六项中，暴露于50至500 microM浓度的dGuo使ara-C核苷酸积累增加了160%至3400%。这些数据表明dGuo可能以临床上有用的方式改变ara-C代谢。
