MECHANISM OF INDUCTION OF CHROMOSOMAL-ABERRATIONS BY INHIBITORS OF DNA TOPOISOMERASES

Evidence is provided that antitopoisomerase drugs induce chromosomal aberrations via the formation of DNA double strand breaks. Camptothecin, an inhibitor of DNA topoisomerase I, produced only chromatid-type aberrations, and in order to be effective it has to be present during the DNA replication. The fact that it induces chromosomal aberrations also in the G2 phase of the cell cycle suggests the presence of a residual DNA synthesis in this phase. A pretreatment with aphidicolin, an inhibitor of DNA polymerases, reduces the camptothecin induced aberrations in the G2 phase, confirming the need of DNA synthesis for the induction of aberrations by the inhibitor of DNA topoisomerase I. (C) 1993 Wiley-Liss, Inc.