Effect of 2'-deoxycoformycin on the inhibition of deoxyribonucleic acid synthesis by 9-beta-D-arabinofuranosyladenine 5'-triphosphate.
Effect of 2'-deoxycoformycin on the inhibition of deoxyribonucleic acid synthesis by 9-beta-D-arabinofuranosyladenine 5'-triphosphate.
复制标题
2-脱氧考福霉素对 9-β-D-阿拉伯呋喃糖腺嘌呤 5-三磷酸抑制脱氧核糖核酸合成的影响。
DOI：
10.1016/0006-2952(82)90427-0
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发表时间：
1982
影响因子：
5.8
通讯作者：
Plunkett,W
中科院分区：
文献类型：
--
作者：
Shewach,DS;Plunkett,W
在 2'-脱氧考福霉素 (dCF)（一种有效的腺苷脱氨酶抑制剂）存在下，9-β-d-阿拉伯呋喃糖腺嘌呤 (ara-A) 细胞毒性增加的生化基础已在 CHO 细胞中进行了研究。 10 微摩尔的 dCF 对该细胞系没有毒性，并且在 24 小时孵育期间，它使 50 μM ara-A 的细胞毒性增加了 7 倍。在没有 dCF 的情况下，CHO 细胞在添加药物后 3 小时内脱氨基超过初始量 ara-A 的 85%。 9-β-d-阿拉伯呋喃糖腺嘌呤 5'-三磷酸 (ara-ATP) 在这些细胞中仅积累 6 小时至 150 μM，此后细胞 ara-ATP 浓度下降。孵育结束时，细胞中未检测到 ara-ATP。相反，dCF 的存在维持了细胞外 ara-A 的高水平，并允许 ara-ATP 在细胞内持续积累。结果表明，dCF 的存在不会改变细胞内 ara-ATP 浓度与细胞 DNA 合成能力 (DSC) 之间的关系。在 75 分钟药物孵育过程中积累的 2.5 μM ara-ATP 浓度对于将 DSC 降低 50% 是必要的。超过400μM ara-ATP的积累不影响四种脱氧核糖核苷三磷酸的细胞内浓度。此外，单独与 ara-A 或在 dCF 存在下孵育 3 小时后，DSC 被抑制超过 95%，但在药物洗掉后 6 小时内显着增加。 DSC 恢复到初始值的 25% 以上对应于细胞内 ara-ATP 浓度下降到低于 35 μM。因此，dCF 的存在可以通过允许更多的 ara-ATP 细胞内积累来增加 DSC 抑制的持续时间，从而导致更多的细胞死亡。
A biochemical basis for the increased cytotoxicity of 9-β-d-arabinofuranosyladenine (ara-A) in the presence of 2′-deoxycoformycin (dCF), a potent inhibitor of adenosine deaminase, has been investigated in CHO cells. Ten micromolar dCF was not toxic to this cell line, and it effected a 7-fold increase in the cytotoxicity of 50 μM ara-A during a 24-hr incubation. In the absence of dCF, CHO cells deaminated more than 85% of the initial amount of ara-A within 3 hr after drug addition. 9-β-d-Arabinofuranosyladenine 5′-triphosphate (ara-ATP) accumulated in these cells for only 6 hr to 150 μM, after which time the cellular ara-ATP concentration declined. At the conclusion of the incubation, no ara-ATP was detectable in the cells. In contrast, the presence of dCF maintained high levels of ara-A extracellularly and allowed a continuous intracellular accumulation of ara-ATP. It was demonstrated that the presence of dCF did not alter the relationship between the intracellular ara-ATP concentration and cellular DNA synthetic capacity (DSC). A concentration of 2.5 μM ara-ATP, accumulated during a 75-min drug incubation, was necessary to decrease DSC by 50%. The accumulation of more than 400 μM ara-ATP did not affect the intracellular concentrations of the four deoxyribonucleoside triphosphates. Furthermore, after a 3-hr incubation with ara-A alone or in the presence of dCF, DSC was inhibited more than 95% but increased substantially within 6 hr following drug washout. Recovery of DSC to more than 25% of the initial value corresponded to a decline in intracellular ara-ATP concentration to less than 35 μM. Thus, the presence of dCF can increase the duration of inhibition of DSC by allowing greater intracellular accumulation of ara-ATP, resulting in greater cell death.