Abstract
BackgroundTo 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.MethodsWe 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.ResultsThe 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.ConclusionsThese 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.
Highlights
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
We investigated the role of C225 in modulating the radioresponse of colorectal cancer cells to 125I seed continuous low dose rate irradiation (125I-CLDR) in vitro
Sensitization of LS180 cells to radiation from 125I seeds by C225 To assess the radiation-enhancing effects of C225, the cells were exposed to CLDR from 125I seeds with and without concurrent treatment with 100 nM of C225
Summary
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. High dose rate endorectal brachytherapy has emerged as an alternative neoadjuvant treatment for low-lying rectal cancer [3,4,5]. We found that brachytherapy with low dose 125-iodine (125I) seeds could serve as an effective salvage therapy for recurring rectal cancer [6]. There are several compelling reasons to explore the efficacy of combined therapy of C225 with continuous low dose rate (CLDR) radiation. If C225 could produce a cytotoxic effect and radiosensitization, its effect on reducing cell survival of in colorectal cancer cells can be further increased when combined with CLDR
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