title: Cytotoxic properties of radionuclide-conjugated Cetuximab without and in combination with external irradiation in head and neck cancer cells in vitro.
abstract: OBJECTIVE
  Epidermal growth factor receptor (EGFR) is critically involved in progression and therapy resistance of squamous cell carcinoma (SCC). Albeit EGFR targeting could improve the effect of radiotherapy on patients' outcome, the clinical results failed to meet expectations from preclinical studies. In this work, we evaluated the potential of the radionuclide Yttrium-90 ((90)Y) bound to Cetuximab ((90)Y-Cetuximab) as novel targeting approach for SCC cells in vitro.
  
  
  METHODS
  FaDu and A431 cell lines were used. EGFR subcellular localization, clonogenic survival, radiation-induced γH2AX foci and EGFR signaling were examined. Cells were treated with DTPA, DTPA-Cetuximab, (90)Y and (90)Y-Cetuximab alone or in combination with external X-ray irradiation.
  
  
  RESULTS
  Dose- and cell line-dependently, (90)Y-Cetuximab mediated a significant reduction in clonogenicity relative to unbound (90)Y. Combined 2-Gy external radiation plus 2-Gy equivalent dose of (90)Y-Cetuximab was more effective than equivalent doses of (90)Y and X-ray radiation. Analogous effects were observed in the number of residual radiation-induced foci. Additionally, EGFR, ERK1/2 and AKT phosphorylation showed alterations upon different treatments.
  
  
  CONCLUSIONS
  Our findings show that Cetuximab-conjugated (90)Y has a significant potential to eradicate human SCC cells. A combination of radioimmunotherapeutic compounds and external radiotherapy might be a promising treatment strategy for clinical application.
authors.affiliation: OncoRay - National Center for Radiation Research in Oncology, Medizinische Fakultät Carl Gustav Carus.
authors.forename: Iris
authors.initials: I
authors.lastname: Eke
authors.forename: Mirjam
authors.initials: M
authors.lastname: Ingargiola
authors.forename: Claudia
authors.initials: C
authors.lastname: Förster
authors.forename: Leoni A
authors.initials: LA
authors.lastname: Kunz-Schughart
authors.forename: Michael
authors.initials: M
authors.lastname: Baumann
authors.forename: Roswitha
authors.initials: R
authors.lastname: Runge
authors.forename: Robert
authors.initials: R
authors.lastname: Freudenberg
authors.forename: Jörg
authors.initials: J
authors.lastname: Kotzerke
authors.forename: Jan-Martin
authors.initials: JM
authors.lastname: Heldt
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Pietzsch
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.forename: Nils
authors.initials: N
authors.lastname: Cordes
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002452:Cell Count; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D000068818:Cetuximab; D003131:Combined Modality Therapy; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D066246:ErbB Receptors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D058990:Molecular Targeted Therapy; D004369:Pentetic Acid / Q000737:chemistry; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D021381:Protein Transport / Q000187:drug effects / Q000528:radiation effects; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D015021:Yttrium Radioisotopes / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D015021:Yttrium Radioisotopes; D004369:Pentetic Acid; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab
keywords: Cetuximab; EGFR; Targeted radioimmunotherapy; radionuclide