Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas: inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis.
We have recently demonstrated that molecular blockade of the epidermal growth factor receptor with the anti-epidermal growth factor receptor (EGFR) monoclonal antibody C225 enhances the in vitro radiosensitivity of human squamous cell carcinomas (SCCs) derived from the head and neck. In the present study, we further investigated the capacity of C225 to modulate the in vitro and in vivo radiation response of human SCC tumor cells and xenografts, and we examined several potential mechanisms that may contribute to the enhanced radiation response induced by C225. Tumor xenograft studies demonstrated complete regression of both newly established (20 mm3) and well-established (100 mm3) SCC tumors over a 55-100 day follow-up period in athymic mice treated with the combination of C225 (i.p. injection) and radiation. Cell cycle analysis via flow cytometry confirmed that combined treatment with C225 and radiation induced an accumulation of cells in the more radiosensitive cell cycle phases (G1, G2-M) with concurrent reduction in the proportion of cells in the more radioresistant S phase. Results from sublethal damage repair and potentially lethal damage repair analyses in cultured SCC cells demonstrated a strong inhibitory effect of C225 on postradiation damage repair. Further, exposure of SCC cells to C225 induced a redistribution of DNA-dependent protein kinase from the nucleus to the cytosol, suggesting one potential mechanism whereby C225 may influence the cellular response to radiation. Immunohistochemical analysis of SCC tumor xenografts after systemic administration of C225 demonstrated inhibition of the in vivo expression of tumor angiogenesis markers, including vascular endothelial growth factor and Factor VIII. Taken together, the collective data suggest that the profound in vivo antitumor activity identified in the xenograft setting when C225 is combined with radiation derives from more than simply the antiproliferative and cell cycle effects of EGFR system inhibition. In addition to antiproliferative growth inhibition, EGFR blockade with C225 appears to influence the capacity of human SCCs to effect DNA repair after exposure to radiation, and to express classic markers of tumor angiogenesis.
Huang
S M
SM
Department of Human Oncology, University of Wisconsin School of Medicine and Comprehensive Cancer Center, Madison 53792-0600, USA.
Harari
P M
PM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology* / Q000532:radiotherapy*; D002453:Cell Cycle / Q000187:drug effects* / Q000528:radiation effects; D002467:Cell Nucleus / Q000378:metabolism; D000068818:Cetuximab; D003600:Cytosol / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D004307:Dose-Response Relationship, Radiation; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005169:Factor VIII / Q000096:biosynthesis; D005260:Female; D005434:Flow Cytometry; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology* / Q000532:radiotherapy*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007700:Kinetics; D008222:Lymphokines / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D011836:Radiation Tolerance; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D013347:Subcellular Fractions / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D008222:Lymphokines; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D005169:Factor VIII; D066246:ErbB Receptors; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; D000068818:Cetuximab