Pourquier Philippe, Lansiaux Amélie
Institut Bergonié, université de Bordeaux, France.
Bull Cancer. 2011 Nov;98(11):1287-98. doi: 10.1684/bdc.2011.1474.
Nuclear topoisomerase I (Top1) is involved in the relaxation of DNA supercoiling and plays a pivotal role in the coordination of essential DNA processes such as transcription, replication, DNA recombination and DNA damage signalling. For all these reasons, Top1 has been an attractive target for the development of anticancer drugs, which poison Top1 by trapping the enzyme on its DNA cleavage sites, which results in irreversible DNA lesions that are responsible for their cytotoxicity. They derive from the natural compound camptothecin and two derivatives are approved in the clinic, topotecan and irinotecan; other compounds such as indolocarbazoles and indenoisoquinolines are in development. However, the efficacy of these drugs is often limited by the problem of resistance, which involves various mechanisms at different steps of drug action, from drug transport and/or metabolism to the signalling and/or repair of the DNA lesions that are generated. A better understanding of these mechanisms is a major concern for the future development of new Top1 inhibitors and the identification of biomarkers that could be used to predict tumour response to these drugs in the clinic and to adapt the treatment to each patient.
核拓扑异构酶I（Top1）参与DNA超螺旋的松弛，并在协调诸如转录、复制、DNA重组和DNA损伤信号传导等基本DNA过程中发挥关键作用。鉴于所有这些原因，Top1一直是抗癌药物开发的一个有吸引力的靶点，这些药物通过将酶捕获在其DNA切割位点上来毒害Top1，这会导致不可逆的DNA损伤，从而产生细胞毒性。它们源自天然化合物喜树碱，两种衍生物已在临床上获批，即拓扑替康和伊立替康；其他化合物如吲哚咔唑和茚并异喹啉正在研发中。然而，这些药物的疗效常常受到耐药性问题的限制，耐药性涉及药物作用不同步骤的各种机制，从药物转运和/或代谢到所产生的DNA损伤的信号传导和/或修复。更好地理解这些机制是未来开发新型Top1抑制剂以及鉴定可用于预测临床肿瘤对这些药物的反应并使治疗适合每位患者的生物标志物的主要关注点。
