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. 2005 Aug 19;95(7):614–618. doi: 10.1111/j.1349-7006.2004.tb02496.x

Direct inhibition of EGF receptor activation in vascular endothelial cells by gefitinib (‘Iressa’, ZD1839)

Akira Hirata 1,2, Hisanori Uehara 3, Keisuke Izumi 3, Seiji Naito 2, Michihiko Kuwano 4, Mayumi Ono 1,✉
PMCID: PMC11159076  PMID: 15245600

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 angiogene‐sis 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.

Abbreviations:

Akt

protein kinase B/Akt

bFGF

basic fibroblast growth factor

EGF

epidermal growth factor

EGFR

epidermal growth factor receptor

ERK

extracellular signal‐regulated kinase

HMVE cells

human microvascular endothelial cells

IL‐8

interleukin‐8

TGFa

transforming growth factor α

VEGF

vascular endothelial growth factor

‘Iressa’ is a trademark of the AstraZeneca group of companies.

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