抗癌药物奥沙利铂与DNA分子相互作用的研究

奥沙利铂被称为第三代铂类药物,特别对胃肠道肿瘤具有较好的疗效.目前大多数的研究表明奥沙利铂的主要作用靶点是DNA分子,但它与DNA分子形成的关键结构和作用机制仍处在探索阶段.本研究运用紫外可见吸收光谱和原子力显微镜观察探索奥沙利铂与DNA在活体外的相互作用过程,从而揭示奥沙利铂产生抗癌作用的主要分子结构基础.首先使用紫外光谱研究了较高浓度奥沙利铂与DNA的作用过程.在此基础上,进一步采用原子力显微镜在高定向热解石墨表面观察了不同浓度奥沙利铂与质粒DNA在37℃条件下作用不同时间后的结构形貌变化,分析了奥沙利铂与DNA相互作用的过程.高分辨原子力显微观察结果表明奥沙利铂与DNA作用后可导致质粒DNA的结构发生显著的变化.随着作用时间的增加,DNA分子逐渐由伸展的链状变化为相互缠绕并带有许多结点的紧密结构,最终变化为更紧密的球状结构.本研究结果表明奥沙利铂可通过化学键合作用和静电作用使质粒DNA逐渐凝集为紧密的球状结构,这种结构可能对奥沙利铂的抗癌活性和毒性产生重要影响.

Study on the Interactions Between Anti-Cancer Drug Oxaliplatin and DNA

Oxaliplatin is a third-generation platinum derivative which is especially efficient for gastric and colorectal cancer treatment. Most studies revealed that the target of oxaliplatin is DNA molecule. However, the key structures formed by oxaliplatin and DNA still controversial so far. In this study, the interactions between oxaliplatin and DNA in vitro have been studied by UV spectra and atomic force microscopy (AFM) so as to reveal the structural basis of its anticancer activity. The structural characteristic after the incubation oxaliplatin at different concentrations with DNA for different time was investigated on freshly cleaved highly ordered pyrolytic graphite (HOPG) surface by atomic force microscopy (AFM). Based on the observed results, the interaction mechanism between oxaliplatin and DNA was proposed. High resolution AFM observation indicated that oxaliplatin can induce structural changes of pUC19 DNA from the extended chains to the intertangled structures with many nodes, and finally to a compact particle after 24 h incubation. The present results revealed that electrostatic and coordination interactions are important to condense plasmid DNA to a compact particle which may significantly influence the activity and cytotoxicity of oxaliplatin.