Genotoxicity of several clinically used topoisomerase II inhibitors

DNA topoisomerase II is an essential nuclear enzyme that modulates DNA topo logy during multiple cellular processes such as DNA replication and chromos ome segregation. Several important clinical antitumor drugs and antibiotics act through inhibition of topoisomerase II. There are a number of differen t steps in the action of topoisomerase II, all of which are potential targe ts for inhibition through drugs and also for cellular and genetic toxicity as well as for mutagenesis. We have investigated and compared the genotoxic ity and mutagenicity of the mechanistically different topoisomerase II inhi bitors m-amsacrine, mitoxantrone, etoposide, genistein, ICRF 193, and beren il using the in vitro micronucleus test, single cell gelelectrophoresis (co met assay) and the mutation assay (tk-locus) in L5178Y mouse lymphoma cells . All six compounds induced micronuclei and all except berenil were mutagen ic. M-amsacrine, mitoxantrone, etopside and genistein induced DNA migration in the comet assay, whereas ICRF 193 was only weakly positive and berenil was negative in this test. Our results are in good agreement with the compo unds' proposed mechanisms of interaction with topoisomerase II. (C) 2000 El sevier Science Ireland Ltd. All rights reserved.