title: Gefitinib (Iressa, ZD1839) inhibits SN38-triggered EGF signals and IL-8 production in gastric cancer cells.
abstract: Epidermal growth factor receptor (EGFR) and its ligands are involved in tumor growth, metastasis, angiogenesis, and resistance to chemotherapy. In the experiments described here using AGS gastric cancer cells, SN38 (the active metabolite of CPT-11) induced tyrosine phosphorylation of EGFR within 5 min, and this was followed by the induction of transcripts and/or proteins of heparin-binding EGF-like growth factor, amphiregulin, transforming growth factor-alpha, and interlukin-8 (IL-8). SN38 also activates nuclear factor-kappaB and activator protein-1, both of which are critical for the transcription of the IL-8 gene. However, the blocking of EGFR activation by gefitinib (Iressa, ZD1839), an EGFR-TKI (tyrosine kinase inhibitor), abrogates all the above reactions. The SN38-triggered mechanisms include the generation of reactive oxygen species (ROS) and the activation of protein kinase C (PKC), followed by metalloproteinase activation and the sequential ectodomain shedding of EGFR ligands. These findings suggest that EGF signaling is enhanced by CPT-11 and point to the potential benefit of the use of a combination of CPT-11 with gefitinib in the treatment of certain gastric cancers.
authors.affiliation: Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. osamuk@imed2.med.osaka-u.ac.jp
authors.forename: Osamu
authors.initials: O
authors.lastname: Kishida
authors.forename: Yoshiji
authors.initials: Y
authors.lastname: Miyazaki
authors.forename: Yoko
authors.initials: Y
authors.lastname: Murayama
authors.forename: Miyuki
authors.initials: M
authors.lastname: Ogasa
authors.forename: Tamana
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Kenji
authors.initials: K
authors.lastname: Watabe
authors.forename: Shusaku
authors.initials: S
authors.lastname: Tsutsui
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kiyohara
authors.forename: Iichiro
authors.initials: I
authors.lastname: Shimomura
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
mesh_terms: D066258:Amphiregulin; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D000077156:Gefitinib; D006023:Glycoproteins / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism*; D000077146:Irinotecan; D010766:Phosphorylation; D011799:Quinazolines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013274:Stomach Neoplasms / Q000473:pathology; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D000970:Antineoplastic Agents; D066255:EGF Family of Proteins; D006023:Glycoproteins; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D011799:Quinazolines; D017382:Reactive Oxygen Species; D016211:Transforming Growth Factor alpha; D014443:Tyrosine; D004815:Epidermal Growth Factor; D000077146:Irinotecan; D066246:ErbB Receptors; D000077156:Gefitinib; D002166:Camptothecin