Additive and supraadditive interaction between ionizing radiation and pazelliptine, a DNA topoisomerase inhibitor, in Chinese hamster V-79 fibroblasts.
The cytotoxic effect of the 9-azaellipticine derivative pazelliptine in combination with gamma-ray irradiation was investigated using Chinese hamster V-79 cells in culture. gamma-ray irradiation and drug treatment (1-h drug exposure) were applied at 1-h intervals for partial DNA damage recovery in growth medium. Isobologram analysis of the clonogenic potential gave evidence of supraadditive interaction in the radiation----drug sequence with 10% survival as an endpoint. No synergistic potentiation was observed at higher survival or as pazelliptine was applied first. Pazelliptine abolished the low-dose shoulder characteristic of asynchronous cell response to gamma-rays. Although rejoining of radiation-induced DNA strand breaks was completed at the time of drug exposure, pazelliptine brought about a larger amount of DNA strand breaks in preirradiated than in nonirradiated cells. The time and dose dependencies of DNA strand break formation and repair with radiation and/or pazelliptine were analyzed by neutral and alkaline filter elution. Pazelliptine in the micromolar range showed the same pattern of double-stranded cleavable complex formation as expected of a DNA topoisomerase II-targeting agent. At a low concentration of pazelliptine, however, protein-concealed breaks were mostly in the form of single-stranded adducts. Such single-stranded complexes have been reported to occur with some topoisomerase II-targeting drugs; their properties are also reminiscent of those induced by the topoisomerase I poison, camptothecin. It is proposed that topoisomerase poisoning interacts with the repair of radiation-induced lesions.
Balosso
J
J
Unité 219 INSERM, Institut Curie-Biologie, Orsay, France.
Giocanti
N
N
Favaudon
V
V
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects*; D002999:Clone Cells; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000187:drug effects / Q000528:radiation effects*; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000187:drug effects / Q000528:radiation effects; D005720:Gamma Rays; D007211:Indoles / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology*; D008168:Lung; D059005:Topoisomerase II Inhibitors
D007211:Indoles; D007546:Isoquinolines; D059005:Topoisomerase II Inhibitors; C024256:pazelliptine; D004247:DNA