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Background: To characterize the effect of combined treatment of the anti-epidermal growth factor receptor (EGFR) monoclonal antibody C225 and 125-iodine (125I) seed radiation in human colorectal cancer.Methods: We treated LS180 cells with 125I continuous low dose rate radiation in the presence and absence of 100 nM C225.The clonogenic capacity, cellular proliferation, cell cycle distribution, apoptosis, and molecular pathways of the cells following the treatments were analyzed in vitro.Results: The sensitizer enhancement ratio of C225 was approximately 1.4.Treatment with C225 and radiation alone produced significant inhibition of cell growth, but combination therapy produced greater inhibition than either treatment administered alone.C225 increased the radiation-induced apoptosis and the fraction of γ-H2AX foci positive cells at 48 h after treatment.The Akt phosphorylation level was lower in the cells receiving the combination treatment than in the cells treated with radiation or C225 alone.Conclusions: These findings indicate that C225 sensitizes LS180 cells to 125I seed radiation.Growth inhibition is mediated by inducing apoptosis and not cell cycle arrest.Additionally, we confirmed that C225 impairs DNA repair by reducing the cellular level of the DNA-PKcs and Ku70 proteins.Furthermore, the inhibition of Akt signaling activation may be responsible for the C225-mediated radiosensitization.