Synergistic effects of combination with fludarabine and carboplatin depend on fludarabine-mediated inhibition of enhanced nucleotide excision repair in leukemia
Synergistic effects of combination with fludarabine and carboplatin depend on fludarabine-mediated inhibition of enhanced nucleotide excision repair in leukemia
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DOI：
10.1007/s12185-011-0930-8
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发表时间：
2011-10-01
影响因子：
2.1
通讯作者：
Ueda, Takanori
中科院分区：
文献类型：
--
作者：
Takagi, Kazutaka;Kawai, Yasukazu;Ueda, Takanori
尽管迄今为止已经引入了几种挽救方案，但克服耐药性仍然是治愈复发性或难治性淋巴瘤并为患者获得有益的长期预后的主要障碍。我们的最终目的是建立一个标准的二线挽救化疗方案来治愈复发/难治性淋巴瘤。在这项基本的临床前研究中，我们评估了由 9-β-D-阿拉伯呋喃糖基-2-氟腺嘌呤 (F-araA) 和卡铂组成的联合方案，该方案在体外针对五个代表性白血病谱系的 DNA 核苷酸切除修复 (NER)。等效线图分析表明，同时暴露于这两种药物会在 U937 和 K562 细胞中产生协同相互作用，通过测量 UV 或药物诱导的 DNA 链断裂（彗星测定）或定量 ERCC1 mRNA（RT-PCR）（NER 的关键酶），这些细胞系显示出增强的 NER 活性。组蛋白 γ H2AX 的形成是协同诱导的，但在 K562 细胞中单独暴露于任一试剂后没有观察到这种形成。总之，我们通过使用 F-araA 和卡铂联合治疗白血病细胞，协同抑制了白血病细胞的 NER 活性，表明这种联合方案可用作难治性或耐药性淋巴瘤的新型挽救疗法。
Overcoming drug resistance remains a major obstacle to curing relapsed or refractory lymphoma and obtaining a beneficial long-term prognosis for patients, despite the introduction of several salvage regimens to date. Our ultimate purpose is to establish a standard second-line salvage chemotherapy regimen for curing relapsed/refractory lymphoma. In this basic pre-clinical study, we evaluated a combination regimen consisting of 9-beta-D-arabinofuranosyl-2-fluoroadenine (F-araA) and carboplatin that targeted nucleotide excision repair (NER) of DNA in five representative leukemia lineages in vitro. Isobologram analysis demonstrated that simultaneous exposure to these two drugs produced synergistic interactions in U937 and K562 cells, in which lines showed enhanced NER activity by the measurement of UV or drug-induced DNA strand break (comet assay), or quantitation of ERCC1 mRNA (RT-PCR), a key enzyme for NER. Histone gamma H2AX formation was synergistically induced, but no such formation was observed after exposure to either agent alone in K562 cells. In summary, we synergistically inhibited the NER activity of leukemia cells by treating them with a combination of F-araA and carboplatin, suggesting that this combinatory regimen could be used as a novel salvage therapy for refractory or drug-resistant lymphoma.