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中科院物理研究所/北京凝聚态物理国家实验室软物质物理实验室利用单分子方法研究抗癌药物顺铂与DNA的作用，取得新进展。该工作部分结果已发表于近期的《核酸研究》（Nucleic Acids Research 37(2009)1400-1410）。 顺铂(cisplatin)是临床上广泛应用的一种抗癌药物，对多种恶性肿瘤（如膀胱癌、前列腺癌、睾丸癌、肺癌、头颈部癌、乳腺癌、卵巢癌、恶性淋巴瘤等）有治疗作用。它含有一个铂原子、两个氯原子和两个氨分子，是一种无机络合物，结构非常简单。但它的抗癌作用机制还没有被完全研究清楚。通常认为顺铂是通过与癌细胞中的DNA结合，形成链内、链间连结，影响DNA的功能，干扰DNA复制、转录等，从而消灭肿瘤。 研究人员利用原子力显微镜(AFM)和磁镊研究了抗癌药物顺铂对单个DNA分子结构的影响。发现在低浓度顺铂作用下，DNA变得比自然状态下更为柔软，DNA的驻留长度(persistence length)从大约52纳米急剧减小为大约15纳米。在高浓度顺铂情况下，发现了DNA的成环和凝聚现象。根据实验结果，研究人员提出顺铂导致的DNA凝聚现象是分层次进行的：第一步，顺铂双臂加合物(di-adduct)导致DNA局部弯折形变；第二步，通过较远的交联形成DNA微环（大小约20纳米）；第三步，通过更远的交联形成大的DNA聚集体；最后，DNA分子凝聚成紧密的小球团。从第二步开始，顺铂单臂加合物(mono-adduct)起重要作用（如图）。基于AFM成像和单分子拉伸两方面的实验结果，他们提出一个顺铂导致的DNA变软(softening)-成环(looping)-缩短(shortening)-凝聚(condensing)模型（简写为SLSC模型）来解释观察到的DNA凝聚过程。他们认为通过远程交联使DNA形成小环结构是铂类抗癌药物作用的重要特征。他们揭示的药物导致的单分子DNA成环及凝聚现象也许是顺铂抗癌的一个关键要素。 该项研究得到了国家自然科学基金、中科院创新工程和国家重点基础研究发展计划的资助。 推荐原始出处： Nucleic Acids Research, 2009, Vol. 37, No. 5 1400-1410 Cisplatin induces loop structures and condensation of single DNA molecules Xi-Miao Hou, Xing-Hua Zhang, Kong-Ji Wei, Chao Ji, Shuo-Xing Dou, Wei-Chi Wang, Ming Li and Peng-Ye Wang* Laboratory of Soft Matter Physics, Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China Structural properties of single DNA treated with anti-cancer drug cisplatin were studied with magnetic tweezers and AFM. Under the effect of low-concentration cisplatin, the DNA became more flexible, with the persistence length decreased significantly from 52 to 15 nm. At a high drug concentration, a DNA condensation phenomenon was observed. Based on experimental results from both single-molecule and AFM studies, we propose a model to explain this kind of DNA condensation by cisplatin: first, di-adducts induce local distortions of DNA. Next, micro-loops of 20 nm appear through distant crosslinks. Then, large aggregates are formed through further crosslinks. Finally, DNA is condensed into a compact globule. Experiments with Pt(dach)Cl2 indicate that oxaliplatin may modify the DNA structures in the same way as cisplatin. The observed loop structure formation of DNA may be an important feature of the effect of platinum anti-cancer drugs that are analogous to cisplatin in structure. (责任编辑：Doctor001) |
