Mechanism of action of DNA topoisomerase inhibitors

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Abstract
DNA topoisomerases are enzymes that regulate DNA topology and are essential for the integrity of the genetic material during transcription, replication and recombination processes. Inhibitors of the mammalian enzymes are widely used antitumor drugs. They stabilize topoisomerase-DNA cleavable complexes by hindering the DNA relegating step of the catalytic reaction, thus resulting in DNA cleavage stimulation. Investigations on the sequence selectivity of DNA cleavage stimulated by chemically unrelated compounds established that specific nucleotides flanking strand cuts are required for drug action. Moreover, structure-activity relationship studies have identified structural determinants of drug sequence specificities, thus eventually allowing the design of new agents targeted at selected genomic regions. The initial cellular lesion, i.e., the drug-stabilized cleavable complex, is a reversible molecular event; however, how it may lead to cell death remains to be fully clarified. Several laboratories focused in past years on molecular and genetic aspects of drug-activated apoptosis. Irreversible double-stranded DNA breaks, generated from collisions between cleavable complexes and advancing replication forks, were suggested to increase p53 protein levels, thus triggering the cell death program. Other genes were also shown to cooperate in modulating the cell response to drug treatments. Recently, several groups have evaluated the possible prognostic value of topoisomerase II levels in solid tumors and hematopoietic neoplasms. Topoisomerase II inhibitors may also have genotoxic effects. Secondary leukemias, characterized by a translocation between chromosomes 11 and 9, have been reported in disease-free patients after treatments with drug regimens that included anti-topoisomerase II agents. It has been proposed that an impairment of topoisomerase activity may be involved in the molecular pathogenesis of secondary leukemias.