Antitumor Inhibitors of DNA Topoisomerases

DNA topoisomerases are nuclear enzymes that regulate DNA topology during transcription , replication and recombination processes, and are essential for the integrity of the genetic material. Eukaryotic DNA topoisomerases are the cellular targets of important antitumor drugs, such as intercalating agents, minor-groove binders and others. These agents interfere with topoisomerases by forming ternary DNA-drug-enzyme complexes in which DNA strands are broken and protein-linked. Topoisome-rase can be diveded into two mechanistic classes: type I and type II DNA enzymes. One type I, and two type II topoisomerases are present in human cells. The expression of the two human topoisomerase II isozymes, encoded by two distinct genes, are differentially modulated during cell proliferation and development. In recent years, x-ray diffraction studies as well as molecular and analyses have allowed to progress in the understanding of the structure and function of DNA topoisomerases. Drug structural genetic determinants have been partially elucidated by studing the DNA sequence specificity of drug stimulation of topoisomerase II DNA cleavage and by novel structure-activity relationship studies, thus eventually allowing the design of new agents targeted at selected genomic regions. Moreover, recent investigations on topoisomerase II inhibitors that do not stimulate DNA cleavage demonstrated that these agents may act against topoisomeras with a novel mechanism, thus suggesting new screening strategies to identify potential antitumor drugs. The initial cellular lesion, i.e. the drug-stabilised cleavable complex, is a reversible molecular event, however how it can lead to cell death remains to be fully understood. Irreversible double-stranded DNA breaks, generating from collisions between cleavable complexes and ongoing DNA-dependent processes may be the trigger of the cell death programme. This review will summarize and discuss recent advances in the molecular pharmacology of antitumor topoisomerase inhibitors.