IMPORTANCE OF REPLICATION FORK PROGRESSION FOR THE INDUCTION OF CHROMOSOME-DAMAGE AND SCE BY INHIBITORS OF DNA TOPOISOMERASES

Previous studies have shown the importance of DNA replication fork progression for the cytotoxicity of topoisomerase inhibitors. Nevertheless, while it was concluded that an interference of moving forks with drug-stabilized topo I-DNA complexes is critical for cell death, in the case of topo II only a partial contribution to cell killing was proposed. We have studied the influence of inhibition of DNA replication by aphidicolin on the production of chromosomal aberrations and SCE by topoisomerase inhibitors. Our results seem to indicate that fork progression is necessary for both cytogenetic endpoints. Pulsed field gel electrophoresis also confirmed this conclusion at the level of DNA breakage (double-strand breaks) efficiently induced by m-AMSA treatment alone, but not when aphidicolin was present. Differences found between topo I and topo II inhibitors (camptothecin and m-AMSA, respectively) could be explained as due to differences in their persistence in trapping the 'cleavable complex'.