title: Efficacy of a triple treatment with irradiation, agonistic TRAIL receptor antibodies and EGFR blockade.
abstract: OBJECTIVE
  : Since the efficacy of a single targeted agent in combination with ionizing radiation is limited by putative treatment resistances, a rationally designed triple treatment consisting of an agonistic antibody targeting either TRAIL-R1 (mapatumumab) or TRAIL-R2 (lexatumumab), radiation and an epidermal growth factor receptor-(EGFR-)inhibiting antibody (cetuximab) was tested.
  
  
  METHODS
  : Induction of apoptosis after triple treatment was determined in Colo205, HCT116 and FaDu cells by Hoechst 33342 stain. The degree of interaction was determined by isobologram analysis. A knockout variant of HCT116 was used to examine Bax dependence of the triple treatment. The role of Akt/PKB signaling was analyzed using the phosphatidylinositol 3-kinase inhibitor LY294002. Clonogenic assays were performed to examine the effect on clonogenic survival of tumor cells.
  
  
  RESULTS
  : A synergistic effect of radiation, cetuximab and agonistic TRAIL-R antibodies was demonstrated in cell lines derived from colorectal tumors or head-and-neck cancers. The efficacy of this multimodal approach was dependent on Bax and inhibition of Akt/PKB in the cell systems used. The results also show a positive impact on clonogenic cell death in several cell lines.
  
  
  CONCLUSIONS
  : These data suggest that rationally designed multimodal therapy approaches integrating radiation with more than one targeted agent will open new perspectives in radiation oncology.
authors.affiliation: Department of Radiation Oncology, CCC Tübingen, Tübingen, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Niyazi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Marini
authors.forename: Peter T
authors.initials: PT
authors.lastname: Daniel
authors.forename: Robin
authors.initials: R
authors.lastname: Humphreys
authors.forename: Verena
authors.initials: V
authors.lastname: Jendrossek
authors.forename: Claus
authors.initials: C
authors.lastname: Belka
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000503:physiopathology / Q000532:radiotherapy*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D020266:Radiotherapy, Conformal / Q000379:methods*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C510234:lexatumumab; D066246:ErbB Receptors; D000068818:Cetuximab; C507357:mapatumumab