MUTAGENIC PROPERTIES OF TOPOISOMERASE-TARGETED DRUGS

Topoisomerases maintain DNA structure by relieving torsional stress oc curring in DNA during transcription, replication and cell division. To poisomerases are of two main types, causing transient breaks in one (t ype I) or both (type II) and strands of DNA, and a number of clinical anticancer drugs are thought to act by inhibiting religation of these transient breaks. Topoisomerase II appears to have a close association with the SMC (stable maintenance of chromosomes) family of proteins i nvolved in organisation of the chromatin in a series of loops on the p roteinaceous chromosomal scaffold. Inhibition of topoisomerase II func tion can result in deletions of such loops, probably mediated by recip rocal exchange of topoisomerase subunits. Disruption of topoisomerase I and/or II function during DNA replication results in smaller DNA del etions and other mutations, probably arising from non-homologous recom bination. Inhibition of topoisomerase II action during mitosis and mei osis can cause incomplete separation of chromatids and chromosomes, wi th the consequent production of genomic mutations. Topoisomerase-media ted mutagenicity is important because it can lead not only to drug res istance but also to drug-induced secondary cancers. Mutagenicity of to poisomerase-directed agents has been underestimated in the past, since these drugs are not usually capable of reacting covalently with DNA a nd usually have low mutagenicity in microbial assays. 0167-4781/98/$ - see front matter (C) 1998 Elsevier Science B.V. All rights reserved.