MUTAGENICITY OF ANTICANCER DRUGS THAT INHIBIT TOPOISOMERASE ENZYMES

Topoisomerases are enzymes that catalyse the transient breakage and re joining of either one (topo I) or two (topo II) DNA strands, to allow one strand to pass through another and prevent unresolvable tangles du ring processes such as DNA replication. A number of important clinical antitumour agents act through inhibition of topo II enzymes, while so me topo I inhibitors appear likely to enter clinical use. Although the se chemicals do not covalently interact with DNA, they have strong mut agenic potential, generally causing events at the level of the chromos ome rather than that of the gene. Most are recombinogens, may affect g ene expression and can also lead to aneuploidy through effects on chro mosome segregation. Most topo I and topo II inhibitors primarily cause mutagenic events associated with the replication fork. However, at le ast in mitotic chromosomes, topo II enzymes are located at the base of chromosome loops, and topo II inhibitors may facilitate subunit excha nges, leading to major deletions and illegitimate recombinational even ts. There is evidence that programmed cell death provides an alternati ve 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.