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ZD6474 is a novel, orally active inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase, with some additional activity against epidermal growth factor receptor (EGFR) tyrosine kinase. The purpose of this study was to determine the potential of ZD6474 in the control of established experimental lung metastasis and pleural effusions produced by human non-small cell lung cancer (NSCLC) cells. PC14PE6 (adenocarcinoma) and H226 (squamous cell carcinoma) cells express high levels of EGFR and only PC14PE6 cells overexpress VEGF. Neither ZD6474 nor the EGFR tyrosine kinase inhibitor gefitinib inhibit proliferation of PC14PE6 or H226 cells in vitro. Both PC14PE6 and H226 cells inoculated intravenously into nude mice induced multiple lung nodules after 5-7 weeks. In addition, PC14PE6 cells produced bloody pleural effusions. Daily oral treatment with ZD6474 did not reduce the number of lung nodules produced by PC14PE6 or H226 cells, but did reduce the lung weight and the size of lung nodules. ZD6474 also inhibited the production of pleural effusions by PC14PE6 cells. Histological analyses of lung lesions revealed that ZD6474 treatment inhibited activation of VEGFR-2 and reduced tumor vascularization and tumor cell proliferation. Therapeutic effects of ZD6474 were considered likely to be due to inhibition of VEGFR-2 tyrosine kinase because gefitinib was inactive in this model. These results indicate that ZD6474, an inhibitor of VEGFR-2, may be useful in controlling the growth of established lung metastasis and pleural effusions by NSCLC.

Original publication

DOI

10.3727/000000006783981260

Type

Journal article

Journal

Oncol Res

Publication Date

2006

Volume

16

Pages

15 - 26

Keywords

Angiogenesis Inhibitors, Animals, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Cell Proliferation, Endothelium, Vascular, Enzyme-Linked Immunosorbent Assay, ErbB Receptors, Flow Cytometry, Gefitinib, Humans, Immunohistochemistry, Lung Neoplasms, Male, Mice, Mice, Inbred BALB C, Neoplasm Transplantation, Neoplasms, Experimental, Neovascularization, Pathologic, Piperidines, Pleural Effusion, Malignant, Quinazolines, Reverse Transcriptase Polymerase Chain Reaction, Vascular Endothelial Growth Factor Receptor-2