title: The effects of ZD1839 (Iressa), a highly selective EGFR tyrosine kinase inhibitor, as a radiosensitiser in bile duct carcinoma cell lines.
abstract: The signaling pathway that is initiated by binding of epidermal growth factor receptor (EGFR) and results in sustained signaling through PI3K plays an important role in a tumor's response to ionizing radiation. The current in vitro study explored both the effects of ZD1839 (Iressa), a highly selective EGFR tyrosine kinase inhibitor, as a radiosensitiser for bile duct carcinoma cell lines and ZD1839's general effects on cell growth in the same two lines. Secondly, we ensured suppression of radiation-induced phosphorylation of EGFR by ZD1839 using an immunoprecipitation technique. Furthermore, we examined radiation-induced phosphorylation of ERK, p38, JNK, and AKT with or without inhibitor with use of Western blot techniques and performed clonogenic assays to confirm radiosensitivity in the presence of a drug. ZD1839 inhibited cell growth of both cell lines and suppressed radiation-induced phosphorylation of EGFR. After exposure to radiation, there was an increase in phosphorylation of AKT as shown by Western blot. Treatment with either ZD1839 or LY294002 (the latter, a PI3K inhibitor) suppressed phosphorylation of AKT by Western blot. Both ZD1839 and LY294002 significantly suppressed colony formation by clonogenic assay; however, U0126 (a MEK1/2 inhibitor), SB203580 (a p38 inhibitor), and SP600125 (a JNK inhibitor) had no effect on colony formation. These results suggest that AKT may be a useful target molecule for enhancement of radiotherapy effect and that ZD1839 may have an important role in combination with radiotherapy for patients with bile duct carcinoma.
authors.affiliation: Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biochemical Research, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Hiroshima 734-8551, Japan. hideki00@hiroshima-u.ac.jp
authors.forename: Hideki
authors.initials: H
authors.lastname: Miyata
authors.forename: Tamito
authors.initials: T
authors.lastname: Sasaki
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kuwahara
authors.forename: Masahiro
authors.initials: M
authors.lastname: Serikawa
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
mesh_terms: D000873:Anthracenes / Q000494:pharmacology; D001650:Bile Duct Neoplasms / Q000378:metabolism / Q000473:pathology; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002867:Chromones / Q000494:pharmacology; D002999:Clone Cells / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000873:Anthracenes; D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009025:Morpholines; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; C113580:U 0126; C432165:pyrazolanthrone; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D066246:ErbB Receptors; D051058:Oncogene Protein v-akt; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D000077156:Gefitinib