Radiosensitization of Ras-mutated human tumor cells in vitro by the specific EGF receptor antagonist BIBX1382BS.

To investigate the cellular and molecular consequences of antagonizing radiation-induced EGFR-activation in vitro.
The effect of the EGFR tyrosine kinase inhibitor BIBX1382BS on radiation sensitivity was determined after single- and fractionated-dose irradiation in human cell lines of bronchial carcinoma (A549), breast adeno-carcinoma (MDA-MB-231), pharyngeal squamous-cell carcinoma (FaDu), squamous-cell carcinoma of cervix (HTB-35) as well as normal (HSF-7) and transformed (HH4-DED) human skin fibroblasts. Applying immuno-precipitation and western blotting pattern of radiation-dependent activation of different components of EGFR-signaling after pre-treatment with and without BIBX1382BS or other tyrosine kinase inhibitors was analyzed.
Autophosphorylation of EGFR which occurred 1-5 min after irradiation (IR, 2 Gy) or treatment with EGF (100 ng/ml) could be inhibited in all cells tested by pre-treatment with BIBX1382BS for 30 min. Combination of drug treatment with fractionated irradiation (4x2 Gy) led to a strong radiosensitizing effect in Ras-mutated A549 and MDA-MB-231 cells, but not in normal Ras presenting cell lines FaDu and HTB-35 or normal and transformed human skin fibroblasts. Both BIBX1382BS as well as the PI3 kinase inhibitor LY294002 led to a blockage (for A549 cells) or reduction (for FaDu cells) of radiation-induced P-AKT. In contrast to FaDu cells, treatment of A549 cells with LY294002 resulted in a significant decrease of post-irradiation survival of A549 cells. Furthermore, only in Ras-mutated cells, but not in normal Ras cells clonogenic survival and phosphorylation of AKT was sensitive to pre-treatment with TGF-alpha-neutralizing antibody indicating an important role of TGF-alpha in regulating radiation-induced EGFR signaling.
Enhancement of radiation sensitivity by the specific EGFR-tyrosine kinase inhibitor BIBX1382BS is not generally achieved in human tumor cells, but depends most likely on the Ras genotype of the cell lines tested.
AuthorsMahmoud Toulany, Klaus Dittmann, Michael Baumann, H Peter Rodemann
JournalRadiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology (Radiother Oncol) Vol. 74 Issue 2 Pg. 117-29 (Feb 2005) ISSN: 0167-8140 [Print] Ireland
PMID15734199 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • BIBX 1382BS
  • Organic Chemicals
  • Receptor, Epidermal Growth Factor
  • Adenocarcinoma (genetics, pathology)
  • Breast Neoplasms (genetics, pathology)
  • Carcinoma, Squamous Cell (genetics, pathology)
  • Female
  • Genes, ras
  • Genotype
  • Humans
  • Lung Neoplasms (genetics, pathology)
  • Male
  • Neoplasms (genetics, pathology)
  • Organic Chemicals (pharmacology)
  • Pharyngeal Neoplasms (genetics, pathology)
  • Phosphorylation
  • Radiation Tolerance
  • Receptor, Epidermal Growth Factor (antagonists & inhibitors, physiology, radiation effects)
  • Tumor Cells, Cultured
  • Uterine Cervical Neoplasms (genetics, pathology)

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