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中科院物理研究所/北京凝聚態物理國家實驗室軟物質物理實驗室利用單分子方法研究抗癌藥物順鉑與DNA的作用，取得新進展。該工作部分結果已發表于近期的《核酸研究》（Nucleic Acids Research 37(2009)1400-1410）。 順鉑(cisplatin)是臨床上廣泛應用的一種抗癌藥物，對多種惡性腫瘤（如膀胱癌、前列腺癌、睪丸癌、肺癌、頭頸部癌、乳腺癌、卵巢癌、惡性淋巴瘤等）有治療作用。它含有一個鉑原子、兩個氯原子和兩個氨分子，是一種無機絡合物，結構非常簡單。但它的抗癌作用機制還沒有被完全研究清楚。通常認為順鉑是通過與癌細胞中的DNA結合，形成鏈內、鏈間連結，影響DNA的功能，干擾DNA復制、轉錄等，從而消滅腫瘤。 研究人員利用原子力顯微鏡(AFM)和磁鑷研究了抗癌藥物順鉑對單個DNA分子結構的影響。發現在低濃度順鉑作用下，DNA變得比自然狀態下更為柔軟，DNA的駐留長度(persistence length)從大約52納米急劇減小為大約15納米。在高濃度順鉑情況下，發現了DNA的成環和凝聚現象。根據實驗結果，研究人員提出順鉑導致的DNA凝聚現象是分層次進行的：第一步，順鉑雙臂加合物(di-adduct)導致DNA局部彎折形變；第二步，通過較遠的交聯形成DNA微環（大小約20納米）；第三步，通過更遠的交聯形成大的DNA聚集體；最后，DNA分子凝聚成緊密的小球團。從第二步開始，順鉑單臂加合物(mono-adduct)起重要作用（如圖）。基于AFM成像和單分子拉伸兩方面的實驗結果，他們提出一個順鉑導致的DNA變軟(softening)-成環(looping)-縮短(shortening)-凝聚(condensing)模型（簡寫為SLSC模型）來解釋觀察到的DNA凝聚過程。他們認為通過遠程交聯使DNA形成小環結構是鉑類抗癌藥物作用的重要特征。他們揭示的藥物導致的單分子DNA成環及凝聚現象也許是順鉑抗癌的一個關鍵要素。 該項研究得到了國家自然科學基金、中科院創新工程和國家重點基礎研究發展計劃的資助。 推薦原始出處： 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. (責任編輯：Doctor001) |
