中科院物理研究所/北京凝聚態(tài)物理國(guó)家實(shí)驗(yàn)室軟物質(zhì)物理實(shí)驗(yàn)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(jìn)展,。該工作部分結(jié)果已發(fā)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(yīng)用的一種抗癌藥物,，對(duì)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(gè)鉑原子,、兩個(gè)氯原子和兩個(gè)氨分子,，是一種無(wú)機(jī)絡(luò)合物,，結(jié)構(gòu)非常簡(jiǎn)單,。但它的抗癌作用機(jī)制還沒(méi)有被完全研究清楚。通常認(rèn)為順鉑是通過(guò)與癌細(xì)胞中的DNA結(jié)合,，形成鏈內(nèi)、鏈間連結(jié),，影響DNA的功能,，干擾DNA復(fù)制,、轉(zhuǎn)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(duì)單個(gè)DNA分子結(jié)構(gòu)的影響。發(fā)現(xiàn)在低濃度順鉑作用下,，DNA變得比自然狀態(tài)下更為柔軟,，DNA的駐留長(zhǎng)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(fā)現(xiàn)了DNA的成環(huán)和凝聚現(xiàn)象,。根據(jù)實(shí)驗(yàn)結(jié)果,，研究人員提出順鉑導(dǎo)致的DNA凝聚現(xiàn)象是分層次進(jìn)行的：第一步，順鉑雙臂加合物(di-adduct)導(dǎo)致DNA局部彎折形變,；第二步,，通過(guò)較遠(yuǎn)的交聯(lián)形成DNA微環(huán)（大小約20納米）；第三步,，通過(guò)更遠(yuǎn)的交聯(lián)形成大的DNA聚集體,；最后,，DNA分子凝聚成緊密的小球團(tuán),。從第二步開(kāi)始，順鉑單臂加合物(mono-adduct)起重要作用（如圖）,?；贏FM成像和單分子拉伸兩方面的實(shí)驗(yàn)結(jié)果，他們提出一個(gè)順鉑導(dǎo)致的DNA變軟(softening)-成環(huán)(looping)-縮短(shortening)-凝聚(condensing)模型（簡(jiǎn)寫(xiě)為SLSC模型）來(lái)解釋觀察到的DNA凝聚過(guò)程,。他們認(rèn)為通過(guò)遠(yuǎn)程交聯(lián)使DNA形成小環(huán)結(jié)構(gòu)是鉑類(lèi)抗癌藥物作用的重要特征,。他們揭示的藥物導(dǎo)致的單分子DNA成環(huán)及凝聚現(xiàn)象也許是順鉑抗癌的一個(gè)關(guān)鍵要素。
該項(xiàng)研究得到了國(guó)家自然科學(xué)基金,、中科院創(chuàng)新工程和國(guó)家重點(diǎn)基礎(chǔ)研究發(fā)展計(jì)劃的資助,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
