ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase.
Epidermal growth factor receptor (EGFR) tyrosine kinase is a potential target for anticancer therapy. ZD1839 (Iressa) is a selective inhibitor of EGFR tyrosine kinase. In this study, we investigated the question as to whether the antitumor effect of ZD1839 is partly attributable to antiangiogenic activity and the potential mechanisms involved. Both ZD1839 and SU5416 [a vascular endothelial growth factor (VEGF)-receptor tyrosine kinase inhibitor] inhibited the migration of human umbilical vein endothelial cell cocultivated with EGF-stimulated cancer cells. ZD1839 also inhibited EGF-induced migration and the formation of tube-like structures by human microvascular endothelial cells. Moreover, ZD1839 almost completely blocked EGF-induced neovascularization of mice cornea, and SU5416 partially blocked neovascularization. In contrast, ZD1839 did not inhibit VEGF-induced angiogenesis. However, EGF-induced up-regulation of the angiogenic factors, VEGF and IL-8, was almost completely blocked by ZD1839. The antitumor effects of ZD1839 could, therefore, be mediated in part by the inhibition of tumor angiogenesis through direct effects on microvascular endothelial cells that express EGFR and also through reduced production of proangiogenic factors by tumor cells.
Hirata
Akira
A
Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Ogawa
Soh-ichiro
S
Kometani
Takuro
T
Kuwano
Takashi
T
Naito
Seiji
S
Kuwano
Michihiko
M
Ono
Mayumi
M
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003315:Cornea / Q000098:blood supply; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014846:Vulvar Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D016209:Interleukin-8; D008222:Lymphokines; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020929:Mitogen-Activated Protein Kinase Kinases; D000077156:Gefitinib