生物谷报道：来自荷兰Delft大学Kavli纳米科学研究所的科学家们最近在研究癌症抑制剂topotecan的工作机制方面取得了重大进展。在这之前，人们对这一抑制剂内在工作机理知之甚少，但Delft的科学家们现在能够观察这种药物对体内单个DNA分子的作用。
以上研究结果发表在本周出版的Nature上。文章第一作者Daniel Koster目前还是Delft的博士生，他将于6月25日接受Delft授予的博士学位，其部分研究结果已经在文章中公布。
研究小组分析的这种重要的癌症抑制剂——topotecan能和一种关键的蛋白质（TopolB）发生相互作用，从而导致癌细胞无法正常工作。蛋白质TopolB的作用主要是移除DNA分子中的环状结构，这会在细胞分裂过程中发生。在这一过程中，TopolB蛋白将和DNA分子结合，然后夹在其周围，并最终切断DNA双链结构中的其中一条，在这之后DNA链将松开，并通过断裂端重新结合到一起。
来自Kavli纳米科学研究所的博士生Daniel Koster、硕士生Elisa Bot以及研究员Nynke Dekker决定用一种非常直接的手段来揭开这其中的内在机理。在实验室中，研究小组将单个DNA分子固定在一个玻璃平板和磁体小球之间。通过两个磁体的帮助，科学家就可以拉动以及扭动DNA分子。结果当小组将TopolB蛋白施加到扭曲的DNA分子上时，科学家们观察到了环被慢慢的移除。
令人意外的是一种TopolB酶对于DNA分子的作用可以被实时观测到。通过和美国St. Jude儿童医院合作，这一机制同样在活体酵母细胞中被观察到。（援引教育部科技发展中心）
相关报道：
Nature advance online publication 24 June 2007 | doi:10.1038/nature05938; Received 6 January 2007; Accepted 15 May 2007; Published online 24 June 2007
Antitumour drugs impede DNA uncoiling by topoisomerase I
Daniel A. Koster1, Komaraiah Palle2, Elisa S. M. Bot1, Mary-Ann Bjornsti2 & Nynke H. Dekker1
Kavli Institute of Nanoscience, Faculty of Applied Sciences, Delft University of Technology, Lorentzweg 1, 2628 CJ Delft, The Netherlands
Department of Molecular Pharmacology, St Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, Tennessee 38105, USA
Correspondence to: Nynke H. Dekker1 Correspondence and requests for materials should be addressed to N.H.D. (Email: n.h.dekker@tudelft.nl).
Increasing the ability of chemotherapeutic drugs to kill cancer cells is often hampered by a limited understanding of their mechanism of action. Camptothecins, such as topotecan, induce cell death by poisoning DNA topoisomerase I, an enzyme capable of removing DNA supercoils1, 2, 3, 4. Topotecan is thought to stabilize a covalent topoisomerase–DNA complex5, 6, 7, rendering it an obstacle to DNA replication forks2, 3, 8, 9. Here we use single-molecule nanomanipulation to monitor the dynamics of human topoisomerase I in the presence of topotecan. This allowed us to detect the binding and unbinding of an individual topotecan molecule in real time and to quantify the drug-induced trapping of topoisomerase on DNA. Unexpectedly, our findings also show that topotecan significantly hinders topoisomerase-mediated DNA uncoiling, with a more pronounced effect on the removal of positive (overwound) versus negative supercoils. In vivo experiments in the budding yeast verified the resulting prediction that positive supercoils would accumulate during transcription and replication as a consequence of camptothecin poisoning of topoisomerase I. Positive supercoils, however, were not induced by drug treatment of cells expressing a catalytically active, camptothecin-resistant topoisomerase I mutant. This combination of single-molecule and in vivo data suggests a cytotoxic mechanism for camptothecins, in which the accumulation of positive supercoils ahead of the replication machinery induces potentially lethal DNA lesions.
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