Inhibition of Translesion DNA Synthesis as a Novel Therapeutic Strategy to Treat Brain Cancer
Inhibition of Translesion DNA Synthesis as a Novel Therapeutic Strategy to Treat Brain Cancer
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DOI：
10.1158/0008-5472.can-17-2464
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发表时间：
2018-02-15
期刊：
影响因子：
11.2
通讯作者：
Berdis, Anthony
中科院分区：
文献类型：
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作者：
Choi, Jung-Suk;Kim, Casey Seol;Berdis, Anthony
替莫唑胺是一种用于治疗脑肿瘤的 DNA 烷化剂，但对该药物的耐药性很常见。在这项研究中，我们提供的证据表明，通过共同施用人工核苷（5-硝基吲哚基-2'-脱氧核苷，5-NIdR）可以显着增强对该药物的有效反应，该人工核苷可有效且选择性地抑制替莫唑胺产生的 DNA 损伤的复制。该化合物在体内转化为相应的核苷三磷酸（5-硝基吲哚基-2'-脱氧核苷三磷酸）可产生多种人类 DNA 聚合酶的有效抑制剂，这些酶可以复制受损的 DNA。因此，5-NIdR 与替莫唑胺协同作用以增加肿瘤细胞的凋亡。在胶质母细胞瘤的小鼠异种移植模型中，替莫唑胺仅延迟肿瘤生长，而与 5-NIdR 联合给药则导致肿瘤完全消退。探索性毒理学研究表明，高剂量的 5-NIdR 不会产生传统核苷类似物常见的副作用。总的来说，我们的结果为协调抑制跨损伤 DNA 合成作为改善侵袭性脑肿瘤化疗反应的策略提供了临床前药理学概念证明。意义：用替莫唑胺和抑制受损 DNA 复制的新型人工核苷联合治疗胶质母细胞瘤可以安全地增强治疗反应。 (C) 2018 年 AACR。
Temozolomide is a DNA-alkylating agent used to treat brain tumors, but resistance to this drug is common. In this study, we provide evidence that efficacious responses to this drug can be heightened significantly by coadministration of an artificial nucleoside (5-nitroindolyl-2'-deoxyriboside, 5-NIdR) that efficiently and selectively inhibits the replication of DNA lesions generated by temozolomide. Conversion of this compound to the corresponding nucleoside triphosphate, 5-nitroindolyl-2'-deoxyriboside triphosphate, in vivo creates a potent inhibitor of several human DNA polymerases that can replicate damaged DNA. Accordingly, 5-NIdR synergized with temozolomide to increase apoptosis of tumor cells. In a murine xenograft model of glio-blastoma, whereas temozolomide only delayed tumor growth, its coadministration with 5-NIdR caused complete tumor regression. Exploratory toxicology investigations showed that high doses of 5-NIdR did not produce the side effects commonly seen with conventional nucleoside analogs. Collectively, our results offer a preclinical pharmacologic proof of concept for the coordinate inhibition of translesion DNA synthesis as a strategy to improve chemotherapeutic responses in aggressive brain tumors.Significance: Combinatorial treatment of glioblastoma with temozolomide and a novel artificial nucleoside that inhibits replication of damaged DNA can safely enhance therapeutic responses. (C) 2018 AACR.