Effect of EGFR Antagonists Gefitinib (Iressa) and C225 (Cetuximab) on MnSOD-Plasmid Liposome Transgene Radiosensitization of a Murine Squamous Cell Carcinoma Cell Line

Abstract

Radiation therapy of tumors of the head and neck region is compromised by dose limiting toxicity of normal tissues including the oral cavity and oropharyngeal mucosa. MnSOD-Plasmid Liposome (MnSOD-PL) intraoral gene therapy has been demonstrated to decrease normal tissue toxicity and also improve survival in mice with orthotopic SCC-VII squamous cell tumors on the floor of the mouth. Furthermore, intravenous administration of MnSOD-PL in mice with orthotopic tumors, or addition of MnSOD-PL to tumor cell lines in vitro produces a radiosensitizing effect attributable to differences in antioxidant pool responses of tumor cells compared to normal tissues following irradiation. To determine whether EGF receptor (EGFR) antagonists Iressa, or Cetuximab provided further improvement of radiation killing of squamous cell tumors, MnSOD-PL transfected or control SCCVII tumor cells were irradiated in vitro, and then the effect of EGFR receptor antagonists was tested. Cells transfected with MnSOD-PL were relatively radiosensitive D₀=1.244±0.126 Gy compared to control D₀=3.246±0.087 (p<0.0001). Clonogenic radiation survival curves of SCCVII cells demonstrated radiosensitization by Iressa D₀=2.770±0.134 Gy (p=0.0264), but no significant radiosensitizing effect of Cetuximab D₀=3.193±0.309 (p=0.7338). The combination of MnSOD-PL plus Iressa further increased radiosensitivity of SCC-VII cells in vitro D₀=0.785±0.01064 (p<0.0001). The results suggest some synergy of the effectiveness of the EGFR antagonist Iressa on increasing the radiation killing of SCC-VII cells that supplements MnSOD-PL tumor radiosensitization.