This chapter discusses the DNA topoisomerases as anticancer drug targets. Much progress has been made in recent years in understanding the mechanism of action of antitumor drugs that target topoisomerases. However, while it is now well established that these drugs interact with the cleavable complex, molecular details of the protein-DNA-drug interaction are only just starting to emerge. The large body of information available from the study of drug analogs has provided some detailed information on the structural requirements for drugs to interact successfully with the cleavable complex. Little is known about the actual cell killing mechanism. This question, which involves events beyond cleavable complex formation and its interaction with drugs, is becoming more and more important. Knowledge of the signals and events involved in cell killing, in particular the early signals induced by drug-mediated DNA damage, might eventually lead to the discovery and identification of new targets for antitumor drugs.
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