Abstract
Malignant pleural effusion (PE) is associated with advanced human lung cancer. We found recently, using a nude mouse model, that vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) is responsible for PE induced by non-small cell human lung carcinoma cells. The purpose of this study was to determine the therapeutic potential of a VEGF/VPF receptor tyrosine kinase phosphorylation inhibitor, PTK 787, against PE formed by human lung adenocarcinoma (PC14PE6) cells. PTK 787 did not affect the in vitro proliferation of PC14PE6 cells, whereas it specifically inhibited proliferation of human dermal microvascular endothelial cells stimulated by VEGF/VPF. A specific platelet-derived growth factor receptor tyrosine kinase inhibitor, CGP57148 (used as a control because PTK 787 also inhibits platelet-derived growth factor receptor tyrosine kinases), had no effect on proliferation of PC14PE6 or human dermal microvascular endothelial cells. i.v. injection of PC14PE6 cells into nude mice produced lung lesions and a large volume of PE containing a high level of VEGF/VPF. Oral treatment with CGP57148 had no effect on PE or lung metastasis. In contrast, oral treatment with PTK 787 significantly reduced the formation of PE but not the number of lung lesions. Furthermore, treatment with PTK 787 significantly suppressed vascular hyperpermeability of PE-bearing mice but did not affect the VEGF/VPF level in PE or expression of VEGF/VPF protein and mRNA in the lung tumors of PC14PE6 cells in vivo. These findings indicate that PTK 787 reduced PE formation mainly by inhibiting vascular permeability, suggesting that this VEGF/VPF receptor tyrosine kinase inhibitor could be useful for the control of malignant PE.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Adenocarcinoma / prevention & control*
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Angiogenesis Inhibitors / pharmacology
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Angiogenesis Inhibitors / therapeutic use*
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Animals
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Capillary Permeability / drug effects
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Cell Division / drug effects
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Cell Line
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Endothelial Growth Factors / genetics
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Endothelial Growth Factors / metabolism
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Endothelial Growth Factors / pharmacology
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / metabolism
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Gene Expression Regulation / drug effects
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Humans
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Immunohistochemistry
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In Situ Hybridization
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Lung Neoplasms / prevention & control*
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Lymphokines / genetics
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Lymphokines / metabolism
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Lymphokines / pharmacology
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Neoplasm Transplantation
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Neovascularization, Pathologic / prevention & control
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Phosphorylation / drug effects
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Phthalazines*
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Pleural Effusion, Malignant / metabolism
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Pleural Effusion, Malignant / prevention & control*
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Pyridines*
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor Protein-Tyrosine Kinases / metabolism
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Receptors, Growth Factor / antagonists & inhibitors*
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Receptors, Growth Factor / metabolism
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Receptors, Vascular Endothelial Growth Factor
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Transplantation, Heterologous
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Tumor Cells, Cultured
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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Angiogenesis Inhibitors
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Endothelial Growth Factors
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Lymphokines
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Phthalazines
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Pyridines
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Receptors, Growth Factor
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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vatalanib
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Receptor Protein-Tyrosine Kinases
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Receptors, Vascular Endothelial Growth Factor