Treatment for Malignant Pleural Effusion of Human Lung Adenocarcinoma by Inhibition of Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Phosphorylation
2000
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.
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