Anticancer effects of ZD6474, a VEGF receptor tyrosine kinase inhibitor, in gefitinib ("Iressa")-sensitive and resistant xenograft models.
ZD6474 is a novel, orally available inhibitor of vascular endothelial growth factor (VEGF) receptor-2 (KDR) tyrosine kinase, with additional activity against epidermal growth factor receptor (EGFR) tyrosine kinase. ZD6474 has been shown to inhibit angiogenesis and tumor growth in a range of tumor models. Gefitinib ("Iressa") is an selective EGFR tyrosine kinase inhibitor (TKI) that blocks signal transduction pathways. We examined the antitumor activity of ZD6474 in the gefitinib-sensitive lung adenocarcinoma cell line, PC-9, and a gefitinib-resistant variant (PC-9/ZD). PC-9/ZD cells showed cross-resistance to ZD6474 in an in vitro dye formation assay. In addition, ZD6474 showed dose-dependent inhibition of EGFR phosphorylation in PC-9 cells, but inhibition was only partial in PC-9/ZD cells. ZD6474-mediated inhibition of tyrosine residue phosphorylation (Tyr992 and Tyr1045) on EGFR was greater in PC-9 cells than in PC-9/ZD cells. These findings suggest that the inhibition of EGFR phosphorylation by ZD6474 can contribute a significant, direct growth-inhibitory effect in tumor cell lines dependent on EGFR signaling for growth and/or survival. The effect of ZD6474 (12.5-50 mg/kg/day p.o. for 21 days) on the growth of PC-9 and PC-9/ZD tumor xenografts in athymic mice was also investigated. The greatest effect was seen in gefitinib-sensitive PC-9 tumors, where ZD6474 treatment (>12.5 mg/kg/day) resulted in tumor regression. Dose-dependent growth inhibition, but not tumor regression, was seen in ZD6474-treated PC-9/ZD tumors. These studies demonstrate that the additional EGFR TKI activity may contribute significantly to the antitumor efficacy of ZD6474, in particular in those tumors that are dependent on continued EGFR-signaling for proliferation or survival. In addition, these results provide a preclinical rationale for further investigation of ZD6474 as a potential treatment option for both EGFR-TKI-sensitive and EGFR-TKI-resistant tumors.
Taguchi
Fumiko
F
Pharmacology Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Koh
Yasuhiro
Y
Koizumi
Fumiaki
F
Tamura
Tomohide
T
Saijo
Nagahiro
N
Nishio
Kazuto
K
D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D000077156:Gefitinib; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010880:Piperidines; D011799:Quinazolines; D014443:Tyrosine; D040262:Receptors, Vascular Endothelial Growth Factor; D000077156:Gefitinib; C452423:vandetanib