Journal
BRITISH JOURNAL OF CANCER
Volume 106, Issue 1, Pages 18-24Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2011.498
Keywords
irinotecan; colorectal cancer; biomarkers; topoisomerase I; TDP1; PARP
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Funding
- Medical Research Council [G0802755] Funding Source: Medline
- MRC [G0802755] Funding Source: UKRI
- Medical Research Council [G0802755] Funding Source: researchfish
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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
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