title: Direct inhibition of EGF receptor activation in vascular endothelial cells by gefitinib ('Iressa', ZD1839).
abstract: The development of gefitinib ('Iressa', ZD1839) by targeting the EGFR tyrosine kinase is a recent therapeutic highlight. We have reported that gefitinib is antiangiogenic in vitro, as well as in vivo. In this study, we asked if the anti-angiogenic action of gefitinib is due to a direct effect on activation of vascular endothelial cells by EGF. EGF, as well as VEGF, caused pronounced angiogenesis in an avascular area of the mouse cornea, and i.p. administration of gefitinib almost completely blocked the response to EGF, but not to VEGF. Immunohistochemical analysis demonstrated phosphorylation of EGFR by EGF in the neovasculature, and gefitinib markedly reduced this effect. Gefitinib also inhibited downstream activation of ERK 1/2 via EGFR in cultured microvascular endothelial (HMVE) cells. These findings suggest that the anti-angiogenic effect of gefitinib in the vascular endothelial cells of neo-vasculature is partly attributable to direct inhibition of EGFR activation, and that endothelial cells in malignant tumors play a critical role in the cancer therapeutic efficacy of gefitinib.
authors.affiliation: Department of Medical Biochemistry, Graduate School of Medical Science, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hirata
authors.forename: Hisanori
authors.initials: H
authors.lastname: Uehara
authors.forename: Keisuke
authors.initials: K
authors.lastname: Izumi
authors.forename: Seiji
authors.initials: S
authors.lastname: Naito
authors.forename: Michihiko
authors.initials: M
authors.lastname: Kuwano
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ono
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D018929:Cell Culture Techniques; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors; D066246:ErbB Receptors / Q000187:drug effects / Q000502:physiology*; D000077156:Gefitinib; D006801:Humans; D007150:Immunohistochemistry; D009389:Neovascularization, Pathologic; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011799:Quinazolines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000077156:Gefitinib