THE SENSITIVITY TO DNA TOPOISOMERASE INHIBITORS IN L5178Y LYMPHOMA STRAINS IS NOT RELATED TO A PRIMARY DEFECT OF DNA TOPOISOMERASES

DNA topoisomerase-targeting antitumor drugs are potent inducers of pro tein-concealed strand breaks in mammalian cells and act by trapping DN A topoisomerases on chromosomal DNA in the form of drug-enzyme-DNA cle avable complexes. It has been proposed that the cleavable complex is a n unusual form of DNA damage that elicits cellular responses analogous to those caused by DNA damaging agents. The relationship between topo isomerase-targeting drug-induced damage and radiation-induced damage h as been investigated by analyzing the properties of DNA topoisomerases in mouse L5178Y lymphoma strains that are cross-sensitive to topoisom erase I-II inhibitors and to UV tight or X-ray irradiation. The strain s are LY-R, isolated from L5178Y cells on the basis of increased resis tance to ionizing radiation, and strain LY-S, isolated from LY-R cells following a spontaneous increase in the sensitivity to ionizing radia tion. LY-S cells, deficient in the rejoining of DNA double-strand brea ks, show enhanced sensitivity to topoisomerase II-targeting inhibitors , whereas LY-R cells have an increased sensitivity to UV radiation and to the topoisomerase I inhibitor, camptothecin. The cellular availabi lity of DNA topoisomerase I and II and the sensitivity of the enzymes to their specific inhibitors have been measured in the two related str ains. In the LY-R strain, we found a 30% decrease in topoisomerase I c ontent but no difference in camptothecin sensitivity, while no quantit ative or qualitative differences were observed for the topoisomerase I I. The results indicate that variations in sensitivity of the L5178Y s trains to topoisomerase inhibitors are unlikely to be related to prima ry defects of the target enzymes, and thus it is possible that common pathways exist for processing of topoisomerase- and radiation-induced damage.