Mutagenicity of anticancer drugs that inhibit topoisomerase enzymes

Topoisomerases are enzymes that catalyse the transient breakage and rejoining of either one (topo I) or two (topo II) DNA strands, to allow one strand to pass through another and prevent unresolvable tangles during processes such as DNA replication. A number of important clinical antitumour agents act through inhibition of topo II enzymes, while some topo I inhibitors appear likely to enter clinical use. Although these chemicals do not covalently interact with DNA, they have strong mutagenic potential, generally causing events at the level of the chromosome rather than that of the gene. Most are recombinogens, may affect gene expression and can also lead to aneuploidy through effects on chromosome segregation. Most topo I and topo II inhibitors primarily cause mutagenic events associated with the replication fork. However, at least in mitotic chromosomes, topo II enzymes are located at the base of chromosome loops, and topo II inhibitors may facilitate subunit exchanges, leading to major deletions and illegitimate recombinational events. There is evidence that programmed cell death provides an alternative pathway to mutagenesis following treatment by either topo I or topo II inhibitors. The final fate of the cell will result from a balance between these two processes.