Inhibition of human DNA polymerase β activity by the anticancer prodrug Cloretazine
Inhibition of human DNA polymerase β activity by the anticancer prodrug Cloretazine
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DOI：
10.1016/j.bbrc.2008.11.042
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发表时间：
2009-01-16
影响因子：
3.1
通讯作者：
Rice, Kevin P.
中科院分区：
文献类型：
--
作者：
Frederick, Abbie M.;Davis, Marguerite L.;Rice, Kevin P.
氯雷他嗪前药通过2-氯乙基化和氨基甲酰化活性之间的协同作用发挥其细胞毒性，所述活性在原位活化时共同产生。本文报道氯雷他嗪抑制纯化的人DNA聚合酶β（Pol β）的核苷酸转移酶活性，Pol β是DNA碱基切除修复（BER）的主要酶。Cloretazine的2-氯乙基化活性在鸟嘌呤碱基的O-6位烷基化DNA，产生2-氯乙氧基鸟嘌呤单加合物，其进一步反应形成细胞毒性链间DNA交联。烷基化DNA通常通过BER在体内修复。Pol β的聚合酶活性的抑制可能是氯雷他嗪的两个反应性亚种在细胞毒性试验中的协同作用的原因。这种抑制作用仅在使用具有氨甲酰化活性的试剂时观察到。此外，虽然治疗相关浓度的氯雷他嗪抑制了Pol β的聚合酶活性，但也可能参与BER的酶的裂解酶活性未被显著抑制。(C)2008年爱思唯尔公司All rights reserved.
The antineoplastic prodrug Cloretazine exerts its cytotoxicity via a synergism between 2-chloroethylating and carbamoylating activities that are cogenerated upon activation in situ. Cloretazine is reported here to inhibit the nucleotidyl-transferase activity of purified human DNA polymerase beta (Pol beta), a principal enzyme of DNA base excision repair (BER). The 2-chloroethylating activity of Cloretazine alkylates DNA at the O-6 position of guanine bases resulting in 2-chloroethoxyguanine monoadducts, which further react to form cytotoxic interstrand DNA crosslinks. Alkylated DNA is often repaired via BER in vivo. Inhibition of the polymerase activity of Pol beta may account for some of the synergism between Cloretazine's two reactive subspecies in cytotoxicity assays. This inhibition was only observed using agents with carbamoylating activity. Furthermore, while therapeutically relevant concentrations of Cloretazine inhibited the polymerase activity of Pol beta, the enzyme's lyase activity, which may also participate in BER, was not significantly inhibited. (C) 2008 Elsevier Inc. All rights reserved.