Pommier Yves
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, 20892-4255, USA.
Nat Rev Cancer. 2006 Oct;6(10):789-802. doi: 10.1038/nrc1977.
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.
核DNA拓扑异构酶I（TOP1）是一种人体必需的酶。它是生物碱喜树碱唯一已知的靶点，强效抗癌药物伊立替康和拓扑替康就是从喜树碱衍生而来的。由于喜树碱类药物结合在TOP1-DNA复合物的界面上，它们代表了可逆捕获大分子复合物的界面抑制剂范例。目前正在研发几种喜树碱和非喜树碱衍生物，以进一步提高抗肿瘤活性并减少副作用。本文综述了肿瘤对TOP1抑制剂反应的机制和分子决定因素，并根据目前对与TOP1介导的DNA损伤相关的修复和检查点途径的了解，考虑了TOP1抑制剂与其他药物的合理联合使用。
