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Review
. 2012 Jan 3;106(1):18-24.
doi: 10.1038/bjc.2011.498. Epub 2011 Nov 22.

Topoisomerase I inhibition in colorectal cancer: biomarkers and therapeutic targets

D C Gilbert  1 , A J Chalmers, S F El-Khamisy
Affiliations
Review

Topoisomerase I inhibition in colorectal cancer: biomarkers and therapeutic targets

D C Gilbert et al. Br J Cancer. .

Abstract

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.

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Figures

Figure 1
Figure 1
(A) Top 1 cleavage complexes are ordinarily removed through TDP1- and PARP-dependent mechanisms, with the ssDNA breaks repaired through XRCC1 and DNA through polymerases/ligases. (B) Camptothecin (and irinotecan via SN38) stabilises the cleavage complexes, with the persistent ssDNA breaks converting to dsDNA lesions causing cell death, and expected synergy with TDP1/PARP inhibition.
See this image and copyright information in PMC

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