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Targeting topoisomerase I: molecular mechanisms and cellular determinants of response to topoisomerase I inhibitors.

BACKGROUND
Topoisomerase I is required for DNA relaxation during critical cellular functions. The identification of camptothecins as specific enzyme inhibitors and their clinical efficacy have stimulated extensive efforts to exploit topoisomerase I as a tumor target and explain the putative mechanisms of antitumor-specific action.


OBJECTIVE
This review provides an overview of the recent achievements in the development of topoisomerase I inhibitors and in the explanation of the biological pathways involved in tumor response.


RESULTS/CONCLUSION
In spite of the difficulty to identify novel topoisomerase I inhibitors with improved pharmacological properties, a growing body of evidence supports the possibility of optimizing the therapeutic profile of available agents. The explanation of defense mechanisms and the molecular determinants of tumor cell response is expected to provide a basis for the design of combination approaches for optimization of topoisomerase I inhibitors-based therapy.