Repair of idarubicin-induced DNA damage: a cause of resistance?
Idarubicin, a widely used anticancer drug inhibits topoisomerase (topo) IIalpha and induces DNA double strand breaks. The finding that idarubicin-induced DNA damage is repaired before cell death is initiated encouraged us to examine the role of DNA repair for the cytotoxicity of idarubicin in human promyelocytic HL60 leukaemia cells. We found that DNA double strand breaks induced by a 90 min transient exposure to 0.5 microgml(-1) idarubicin were rapidly repaired throughout the whole population, while topo IIalpha itself was degraded. In spite of DNA repair, the vast majority of cells died within 40 h. Using differential staining of the chromatids and microscopic evaluation of DNA break points, we found evidence for a high number of false ligations of loose DNA strands arising from the inhibition of topo IIalpha action by idarubicin. If mainly actively transcribed genes are affected, this results in a disruption of vital genetic information, of regulatory sequences and, ultimately, in induction of the cell death pathway. Our results confirm the hypothesis that misrepair of DNA damage is a decisive event in idarubicin-induced cell death. They are discussed in the context of topo IIalpha-function and the currently known mechanisms of DNA double strand break repair.
Dartsch
Dorothee C
DC
Hamburg University, Institute of Pharmacy, Bundesstr. 45, 20146 Hamburg, Germany. dorothee.dartsch@chemie.uni-hamburg.de
Gieseler
Frank
F
D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D000951:Antigens, Neoplasm / Q000378:metabolism; D002453:Cell Cycle; D016923:Cell Death; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair / Q000502:physiology*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015321:Gene Rearrangement; D018922:HL-60 Cells; D006801:Humans; D015255:Idarubicin / Q000633:toxicity*; D008954:Models, Biological; D013997:Time Factors
D000903:Antibiotics, Antineoplastic; D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D004250:DNA Topoisomerases, Type II; D015255:Idarubicin