title: In vitro responsiveness of glioma cell lines to multimodality treatment with radiotherapy, temozolomide, and epidermal growth factor receptor inhibition with cetuximab.
abstract: BACKGROUND
  The majority of glioblastoma multiforme (GBM) cells express the epidermal growth factor receptor (EGFR). The present study evaluates the combination of temozolomide (TMZ), EGFR inhibition, and radiotherapy (RT) in GBM cell lines.
  
  
  METHODS
  Human GBM cell lines U87, LN229, LN18, NCH 82, and NCH 89 were treated with various combinations of TMZ, RT, and the monoclonal EGFR antibody cetuximab. Responsiveness of glioma cells to the combination treatment was measured by clonogenic survival.
  
  
  RESULTS
  Overall, double and triple combinations of RT, TMZ, and cetuximab lead to additive cytotoxic effects (independent toxicity). A notable exception was observed for U87 and LN 18 cell lines, where the combination of TMZ and cetuximab showed substantial antagonism. Interestingly, in these two cell lines, the combination of RT with cetuximab resulted in a substantial increase in cell killing over that expected for independent toxicity. The triple combination with RT, cetuximab, and TMZ was nearly able to overcome the antagonism for the TMZ/cetuximab combination in U87, however only marginally in LN18, GBM cell lines.
  
  
  CONCLUSIONS
  It appears that EGFR expression is not correlated with cytotoxic effects exerted by cetuximab. Combination treatment with TMZ, cetuximab and radiation resulted in independent toxicity in three out of five cell lines evaluated, the antagonistic effect of the TMZ/cetuximab combination in two cell lines could indicate that TMZ preferentially kills cetuximab-resistant cells, suggesting for some cross-talk between toxicity mechanisms. Expression of EGFR was no surrogate marker for responsiveness to cetuximab, alone or in combination with RT and TMZ.
authors.affiliation: Department of Radiation Oncology, University of Heidelberg, Heidelberg, Germany. Stephanie.Combs@med.uni-heidelberg.de
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Combs
authors.forename: Daniela
authors.initials: D
authors.lastname: Schulz-Ertner
authors.forename: Wilfried
authors.initials: W
authors.lastname: Roth
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
authors.forename: Jürgen
authors.initials: J
authors.lastname: Debus
authors.forename: Klaus-Josef
authors.initials: KJ
authors.lastname: Weber
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects* / Q000528:radiation effects*; D000068818:Cetuximab; D017024:Chemotherapy, Adjuvant / Q000379:methods; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D011829:Radiation Dosage; D000077204:Temozolomide
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004815:Epidermal Growth Factor; D003606:Dacarbazine; D000068818:Cetuximab; D000077204:Temozolomide