Oxaliplatin-induced damage of cellular DNA
Oxaliplatin-induced damage of cellular DNA
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DOI：
10.1124/mol.58.5.920
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发表时间：
2000-11-01
影响因子：
3.6
通讯作者：
Juniewicz, PE
中科院分区：
文献类型：
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作者：
Woynarowski, JM;Faivre, S;Juniewicz, PE
对细胞DNA的损伤被认为决定了铂（Pt）药物的抗增殖特性。本研究描述了奥沙利铂（一种具有临床抗肿瘤活性的二氨基环己烷铂类药物）对DNA的损伤。与顺铂相比，奥沙利铂形成的Pt-DNA加合物显著更少（例如，0.86+/- 0.04对1.36 +/- 0.01加合物/10（6）碱基对/10 μ M药物/1小时，在CEM细胞中分别为P <0.01）。发现奥沙利铂可诱导潜在致死性双功能病变，如CEM细胞中的链间DNA交联（ISC）和DNA-蛋白质交联（DPC）。然而，与总加合物一样，奥沙利铂产生的双功能损伤比顺铂少（P <0.05）：治疗4小时后，分别为0.7 +/- 0.2和1.8 +/- 0.3 ISC和0.8 +/- 0.1和1.5 +/- 0.3 DPC/10（6）碱基对/10 μ M药物。延长孵育后（长达12 h）不能补偿奥沙利铂导致的DPC和ISC水平降低。分离的CEM细胞核中的ISC和DPC测定明确证实奥沙利铂形成这些病变的能力固有地低于顺铂。在四种细胞系中观察到的药物处理质粒的再活化表明，奥沙利铂加合物的修复动力学与顺铂加合物相似。然而，奥沙利铂在抑制DNA链延长方面比顺铂更有效（每相等数量的DNA加合物）（与CEM细胞中的7倍相似）。尽管DNA反应性较低，但奥沙利铂在其他几种人肿瘤细胞系中表现出相似或更大的细胞毒性（1.1/1.2 μ M时CEM细胞的生长抑制率分别为50%）。结果表明，奥沙利铂诱导的DNA损伤，包括ISC和DPC，可能有助于药物的生物学特性。然而，奥沙利铂需要比顺铂更少的DNA损伤来实现细胞生长抑制。
Damage to cellular DNA is believed to determine the antiproliferative properties of platinum (Pt) drugs. This study characterized DNA damage by oxaliplatin, a diaminocyclohexane Pt drug with clinical antitumor activity. Compared with cisplatin, oxaliplatin formed significantly fewer Pt-DNA adducts (e.g., 0.86 +/- 0.04 versus 1.36 +/- 0.01 adducts/10(6) base pairs/10 mu M drug/1 h, respectively, in CEM cells, P < .01). Oxaliplatin was found to induce potentially lethal bifunctional lesions, such as interstrand DNA cross-links (ISC) and DNA-protein cross-links (DPC) in CEM cells. As with total adducts, however, oxaliplatin produced fewer (P < .05) bifunctional lesions than did cisplatin: 0.7 +/- 0.2 and 1.8 +/- 0.3 ISC and 0.8 +/- 0.1 and 1.5 +/- 0.3 DPC/10(6) base pairs/10 mu M drug, respectively, after a 4-h treatment. Extended postincubation (up to 12 h) did not compensate the lower DPC and ISC levels by oxaliplatin. ISC and DPC determinations in isolated CEM nuclei unequivocally verified that oxaliplatin is inherently less able than cisplatin to form these lesions. Reactivation of drug-treated plasmids, observed in four cell lines, suggests that oxaliplatin adducts are repaired with similar kinetics as cisplatin adducts. Oxaliplatin, however, was more efficient than cisplatin per equal number of DNA adducts in inhibiting DNA chain elongation (similar to 7 fold in CEM cells). Despite lower DNA reactivity, oxaliplatin exhibited similar or greater cytotoxicity in several other human tumor cell lines (50% growth inhibition in CEM cells at 1.1/1.2 mu M, respectively). The results demonstrate that oxaliplatin-induced DNA lesions, including ISC and DPC, are likely to contribute to the drug's biological properties. However, oxaliplatin requires fewer DNA lesions than does cisplatin to achieve cell growth inhibition.