title: Activity of anti-epidermal growth factor receptor monoclonal antibody C225 against glioblastoma multiforme.
abstract: OBJECTIVE
  Overexpression of epidermal growth factor receptor (EGFR) in glioblastoma multiforme (GBM) secondary to EGFR gene amplification is associated with a more aggressive tumor phenotype and a worse clinical outcome. The purpose of this study was to analyze whether blocking this receptor with the anti-EGFR chimeric monoclonal antibody C225 would decrease proliferation and increase apoptosis in GBM cells.
  
  
  METHODS
  EGFR expression and amplification were analyzed for seven human GBM cell lines. These lines were then exposed to different concentrations of C225 for 48 hours, 72 hours, and 7 days, after which time cytotoxicity, apoptosis, and vascular endothelial growth factor expression were assessed in vitro. Two EGFR-amplified human GBM were implanted in the flanks of nude mice, and the animals received C225 twice per week intraperitoneally for 5 weeks. Tumor volumes and survival times were compared with those of sham-treated mice.
  
  
  RESULTS
  EGFR gene amplification was demonstrated in three of the primary GBM lines. C225 treatment produced significant cytotoxicity in all three EGFR-amplified GBM lines, but not in unamplified lines. Flow cytometry demonstrated increased apoptosis in C225-treated, EGFR-amplified GBM lines, but not in unamplified lines. There was a decrease in vascular endothelial growth factor expression in all GBM lines with exposure to C225. Tumor-bearing mice treated with C225 experienced significant inhibition of tumor growth as well as a 200% increase in median survival.
  
  
  CONCLUSIONS
  Blocking EGFR in GBM cells that overexpress this receptor significantly changes tumor cell biology by promoting apoptosis while decreasing proliferation and vascular endothelial growth factor expression. This approach holds great promise for the treatment of patients with GBMs.
authors.affiliation: Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse 13210, USA. ellerj@upstate.edu
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Eller
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Longo
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hicklin
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Canute
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D000068818:Cetuximab; D016228:Endothelial Growth Factors / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D005784:Gene Amplification; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D008222:Lymphokines / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D016019:Survival Analysis; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D066246:ErbB Receptors; D000068818:Cetuximab