Topoisomerase I inhibition in colorectal cancer: biomarkers and therapeutic targets

被引：82

作者：

Gilbert, D. C. ^{[1
]}

Chalmers, A. J. ^{[2
]}

El-Khamisy, S. F. ^{[3
,4
]}

机构：

[1] Royal Sussex Cty Hosp, Sussex Canc Ctr, Brighton BN2 5BE, E Sussex, England

[2] Univ Glasgow, Inst Canc Sci, Glasgow G12 8QQ, Lanark, Scotland

[3] Univ Sussex, Genome Damage & Stabil Ctr, Brighton BN1 9RQ, E Sussex, England

[4] Ain Shams Univ, Fac Pharm, Dept Biochem, Cairo, Egypt

来源：

BRITISH JOURNAL OF CANCER | 2012年 / 106卷 / 01期

基金：

英国医学研究理事会;

关键词：

irinotecan; colorectal cancer; biomarkers; topoisomerase I; TDP1; PARP; STRAND-BREAK REPAIR; POLY(ADP-RIBOSE) POLYMERASE INHIBITOR; RANDOMIZED CONTROLLED-TRIAL; ADVANCED RECTAL-CANCER; CELL LUNG-CANCER; MICROSATELLITE-INSTABILITY; COLON-CANCER; DNA-DAMAGE; COMBINATION CHEMOTHERAPY; PHARMACODYNAMIC GENES;

D O I：

10.1038/bjc.2011.498

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The topoisomerase I (Top 1) poison irinotecan is an important component of the modern treatment of colorectal cancer. By stabilising Top 1-DNA complexes, irinotecan generates Top 1-linked DNA single-strand breaks that can evolve into double-strand breaks and ultimately cause cell death. However, cancer cells may overcome cell killing by releasing the stalled topoisomerase from DNA termini, thereby reducing the efficacy of Top 1 poisons in clinics. Thus, understanding the DNA repair mechanisms involved in the repair of Top 1-mediated DNA damage provides a useful tool to identify potential biomarkers that predict response to this class of chemotherapy. Furthermore, targeting these pathways could enhance the therapeutic benefits of Top 1 poisons. In this review, we describe the cellular mechanisms and consequences of targeting Top 1 activity in cells. We summarise preclinical data and discuss the potential clinical utility of small-molecule inhibitors of the key proteins. British Journal of Cancer (2012) 106, 18-24. doi:10.1038/bjc.2011.498 www.bjcancer.com Published online 22 November 2011 (C) 2012 Cancer Research UK

引用

页码：18 / 24

页数：7

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