Time and dose-dependent radiosensitization of the glioblastoma multiforme U251 cells by the EGF receptor tyrosine kinase inhibitor ZD1839 ('Iressa').
Hyperactive epidermal growth factor receptor (EGFR) signaling, which promotes unregulated cell growth and inhibits apoptosis, is believed to contribute to clinical radiation resistance of glioblastoma multiforme (GBM). Blockage of the EGFR signalling pathways may offer an attractive therapeutic target to increase the cytotoxic effects of radiotherapy. We report the effects of ZD1839 ('Iressa'), a selective EGFR tyrosine kinase inhibitor on the radiation sensitivity of the U251 GBM cell line, which expresses high levels of EGFR. In radiation survival experiments, 5 microM of ZD1839 had a significant radiosensitizing effect and increased cell death was observed at doses of 5Gy in the presence of ZD1839. Dose and schedule of drug administration in combination with radiation appeared to be a crucial element to obtain radiosensitization of the cells. These studies suggest novel therapeutic strategies in the treatment of GBM.
Stea
Baldassarre
B
Department of Radiation Oncology, Arizona Cancer Center, University of Arizona, 1501 N. Campbell Ave, Tucson, AZ 85724, USA. bstea@azcc.arizona.edu
Falsey
Ryan
R
Kislin
Kerri
K
Patel
Jay
J
Glanzberg
Heather
H
Carey
Steven
S
Ambrad
Aaron A
AA
Meuillet
Emmanuelle J
EJ
Martinez
Jesse D
JD
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D002455:Cell Division / Q000528:radiation effects; D002531:Cerebellum / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077156:Gefitinib; D005909:Glioblastoma / Q000378:metabolism / Q000532:radiotherapy*; D006801:Humans; D010766:Phosphorylation / Q000528:radiation effects; D010920:Placenta / Q000378:metabolism; D011799:Quinazolines / Q000627:therapeutic use*; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D011879:Radiotherapy Dosage; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000528:radiation effects; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D000077156:Gefitinib