MECHANISM OF ACTION OF DNA TOPOISOMERASE INHIBITORS

DNA topoisomerases are enzymes that regulate DNA topology and are esse ntial for the integrity of the genetic material during transcription, replication and recombination processes. Inhibitors of the mammalian e nzymes are widely used antitumor drugs. They stabilize topoisomerase-D NA cleavable complexes by hindering the DNA relegating step of the cat alytic reaction, thus resulting in DNA cleavage stimulation. Investiga tions on the sequence selectivity of DNA cleavage stimulated by chemic ally unrelated compounds established that specific nucleotides flankin g strand cuts are required for drug action. Moreover, structure-activi ty relationship studies have identified structural determinants of dru g sequence specificities, thus eventually allowing the design of new a gents targeted at selected genomic regions. The initial cellular lesio n, i.e., the drug-stabilized cleavable complex, is a reversible molecu lar 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-stra nded DNA breaks, generated from collisions between cleavable complexes and advancing replication forks, were suggested to increase p53 prote in levels, thus triggering the cell death program. Other genes were al so shown to cooperate in modulating the cell response to drug treatmen ts. Recently, several groups have evaluated the possible prognostic va lue of topoisomerase II levels in solid tumors and hematopoietic neopl asms. Topoisomerase II inhibitors may also have genotoxic effects. Sec ondary leukemias, characterized by a translocation between chromosomes 11 and 9, have been reported in disease-free patients after treatment s with drug regimens that included antitopoisomerase II agents. It has been proposed that an impairment of topoisomerase activity may be inv olved in the molecular pathogenesis of secondary leukemias.