dUTPase和uracil-DNA糖基化酶在酿酒酵母antifolate中央调节器的毒性。

文章的细节

引用

复制到剪贴板

Tinkelenberg英航Hansbury MJ,拉RD

dUTPase和uracil-DNA糖基化酶在酿酒酵母antifolate中央调节器的毒性。

癌症研究》2002年9月1;62(17):4909 - 15所示。

PubMed ID

12208740 (在PubMed

]

文摘

thymidylate合酶的反应仍然是一个广泛使用的抗癌药物的重要目标;然而,这些药物的临床效用受到细胞耐药性的发生。尽管大量的信息关于药物作用的机制,导致下游事件的相对重要性杀伤力仍不清楚。在这项研究中,我们已经开发了一个模型系统使用出芽酵母酿酒酵母的影响剖析转储错误插入到DNA的贡献机制引起的细胞毒性antifolate代理。dUTPase的活动和uracil-DNA糖基化酶,uracil-DNA代谢的关键酶,减少或增强,操纵菌株生化端点的毒性进行了分析。细胞overexpressing dUTPase是从细胞毒性的保护能力以防止dUTP池扩张和能够在早期s阶段检查站逮捕。相比之下,损耗dUTPase活动导致的累积dUTP池和增强抗敏感。这些细胞s阶段月初被捕,无法完整的DNA复制后停药,导致致命性。失活的尿嘧啶基地切除修复诱导部分抗细胞毒性早期(10 h内);然而,在之后的时间点杀伤力最终导致(12到24小时),大概是因为稳定的不利影响尿嘧啶错误插入。 Although these cells were able to complete replication with uracil-substituted DNA, they arrested at the G(2)-M phase. This finding may represent a novel mechanism by which the G(2)-M checkpoint is signaled by the presence of uracil-substituted DNA. Together these data provide both genetic and biochemical evidence demonstrating that lethality from antifolates in yeast is primarily dependent on uracil misincorporation into DNA, and that uracil-independent mechanisms associated with dTTP depletion play a minor role. Our findings indicate that the relative expression levels of both dUTPase and uracil-DNA glycosylase can have great influence over the efficacy of thymidylate synthase-directed chemotherapy, thereby enhancing the candidacy of these proteins as prognostic markers and alternative targets for therapeutic development.

beplay体育安全吗DrugBank数据引用了这篇文章

药物

卡培他滨