A comparison of response to cisplatin, radiation and combined treatment for cells deficient in recombination repair pathways.
The responses of cells with mutated DNA repair pathways were compared for cisplatin, radiation and combination treatments. The knockout of the nonhomologous endjoining (NHEJ) pathway resulted in increased radiation sensitivity, but no change in cisplatin response in the mouse cells and increased radiosensitivity but decreased cisplatin sensitivity in chicken cells. The mutation of the homologous recombination repair (HR) pathway through XRCC3 in CHO cells resulted in increased radiation and cisplatin sensitivity and to a lesser extent for the Rad54 knockout in the DT40 chicken cells. The combination treatments of cisplatin and radiation showed that inhibition of the HR repair pathway resulted in super additive effects while the inhibition of the NHEJ pathway in DT40 had no effect. In mouse cells the knockout of the NHEJ pathway resulted in reduced super additivity compared to the parental cell lines. These data show that radiation, cisplatin and combination treatment damage is affected differently by the various DNA repair pathways, which could have a range of effects on combination treatments in tumour cells expressing different levels of DNA repair in the various repair pathways.
Raaphorst
G P
GP
Medical Physics Department, Integrated Cancer Program, The Ottawa Hospital, Ottawa, Ontario, Canada K1H 8L6. graaphorst@ottawahospital.on.ca
Leblanc
Maude
M
Li
L F
LF
D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics; D016466:CHO Cells; D002460:Cell Line; D002645:Chickens; D002945:Cisplatin / Q000494:pharmacology*; D006224:Cricetinae; D004249:DNA Damage / Q000235:genetics; D004265:DNA Helicases; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000187:drug effects* / Q000528:radiation effects*; D000072200:Ku Autoantigen; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics*; D011995:Recombination, Genetic / Q000235:genetics
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C110901:X-ray repair cross complementing protein 3; D004265:DNA Helicases; C103534:Rad54l protein, mouse; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen; D002945:Cisplatin