文章：

拓扑异构酶I抑制剂：喜树碱及其他

Topoisomerase I inhibitors: camptothecins and beyond

原文发布日期：2006-10-01

DOI: 10.1038/nrc1977

类型: Review Article

开放获取: 否

要点：

1. Topoisomerase I (TOP1) enzymes are essential in higher eukaryotes, as they are required to relax DNA supercoiling generated by transcription, replication and chromatin remodelling.
2. Topoisomerases are particularly vulnerable to topoisomerase I inhibitors during their cleavage reaction, which is referred to as the 'cleavage complex'.
3. TOP1 can be trapped by anticancer drugs as it cleaves DNA. Moreover, TOP1 can be trapped by endogenous alterations to DNA (mismatches, abasic sites, nicks and adducts) and apoptotic alterations to chromatin.
4. Camptothecin is a natural product of which TOP1 is the only cellular target. Two camptothecin derivatives have recently been approved by the US Food and Drug Administration: topotecan for ovarian and lung cancers and irinotecan for colorectal cancer.
5. Various non-camptothecin inhibitors of TOP1 are in development, including indolocarbazole, phenanthridine and indenoisoquinoline derivatives. Non-camptothecins are expected to be active in cancers that are currently resistant to camptothecins, and to have a greater therapeutic index.
6. Co-crystal structures of TOP1 inhibitors illustrate the interfacial inhibition paradigm by which a small drug molecule can trap conformational intermediates of macromolecular complexes (in the case of TOP1 inhibitors, the TOP1 enzyme and its cleaved DNA substrate).
7. The cytotoxic activity of TOP1 inhibitors is related to the interference of trapped TOP1 cleavage complexes with DNA replication and transcription.
8. Deficiencies in both the checkpoint and DNA-repair pathways determine cellular sensitivity to TOP1 inhibitors. Therefore, the identification of such deficiencies in tumours should guide the rational use of TOP1 inhibitors. Targeting checkpoint and repair pathways should also increase the selectivity of TOP1 inhibitors in tumours that have pre-existing deficiencies in relevant redundant pathways.

要点翻译：

1. 拓扑异构酶I（TOP1）在高等真核生物中至关重要，因其能缓解转录、复制及染色质重塑产生的DNA超螺旋。
2. 拓扑异构酶在裂解反应期间对拓扑异构酶I抑制剂尤为敏感，该状态被称为"裂解复合物"。
3. 当TOP1切割DNA时，可被抗癌药物捕获。此外，DNA内源性改变（错配、脱碱基位点、缺口及加合物）和染色质凋亡性改变也可捕获TOP1。
4. 喜树碱是一种天然产物，其唯一细胞靶点为TOP1。美国食品药品监督管理局近期批准了两种喜树碱衍生物：拓扑替康用于卵巢癌和肺癌，伊立替康用于结直肠癌。
5. 多种非喜树碱类TOP1抑制剂正在研发中，包括吲哚并咔唑、菲啶和茚并异喹啉衍生物。非喜树碱类药物预计对当前耐喜树碱的癌症具有活性，且具有更佳的治疗指数。
6. TOP1抑制剂的共晶结构阐释了界面抑制范式：小分子药物可通过该机制捕获大分子复合物的构象中间体（就TOP1抑制剂而言，即TOP1酶及其切割的DNA底物）。
7. TOP1抑制剂的细胞毒性活性与受陷TOP1裂解复合物干扰DNA复制和转录相关。
8. 检查点与DNA修复通路缺陷共同决定细胞对TOP1抑制剂的敏感性。因此，检测肿瘤中此类缺陷应能指导TOP1抑制剂的合理应用。靶向检查点与修复通路还有望增强TOP1抑制剂在相关冗余通路已存在缺陷的肿瘤中的选择性。

英文摘要：

Nuclear DNA topoisomerase I (TOP1) is an essential human enzyme. It is the only known target of the alkaloid camptothecin, from which the potent anticancer agents irinotecan and topotecan are derived. As camptothecins bind at the interface of the TOP1–DNA complex, they represent a paradigm for interfacial inhibitors that reversibly trap macromolecular complexes. Several camptothecin and non-camptothecin derivatives are being developed to further increase anti-tumour activity and reduce side effects. The mechanisms and molecular determinants of tumour response to TOP1 inhibitors are reviewed, and rational combinations of TOP1 inhibitors with other drugs are considered based on current knowledge of repair and checkpoint pathways that are associated with TOP1-mediated DNA damage.

摘要翻译： 

核DNA拓扑异构酶I（TOP1）是人类必需的酶，也是生物碱喜树碱（camptothecin）的唯一已知靶点；伊立替康（irinotecan）和拓扑替康（topotecan）等强效抗癌药物均源自喜树碱。由于喜树碱类药物结合于TOP1-DNA复合物的界面，它们成为可逆性捕获大分子复合物的界面抑制剂典范。目前，多种喜树碱及非喜树碱衍生物正在开发中，以进一步提高抗肿瘤活性并降低副作用。本文综述了肿瘤对TOP1抑制剂产生应答的机制与分子决定因素，并基于与TOP1介导的DNA损伤相关的修复及检查点通路的现有知识，探讨了TOP1抑制剂与其他药物合理联合的策略。

原文链接：

Topoisomerase I inhibitors: camptothecins and beyond