Treatment for malignant pleural effusion of human lung adenocarcinoma by inhibition of vascular endothelial growth factor receptor tyrosine kinase phosphorylation
S. Yano et al., Treatment for malignant pleural effusion of human lung adenocarcinoma by inhibition of vascular endothelial growth factor receptor tyrosine kinase phosphorylation, CLIN CANC R, 6(3), 2000, pp. 957-965
Malignant pleural effusion (PE) is associated with advanced human lung canc
er, 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 tyr
osine kinase phosphorylation inhibitor, PTK 787, against PE formed by human
lung adenocarcinoma (PC14PE6) cells. PTK 787 did not affect the in vitro p
roliferation of PC14PE6 cells, whereas it specifically inhibited proliferat
ion of human dermal microvascular endothelial cells stimulated by VEGF/VPF,
A specific platelet-derived growth factor receptor tyrosine kinase inhibit
or, CGP57148 (used as a control because PTK 787 also inhibits platelet-deri
ved growth factor receptor tyrosine kinases), had no effect on proliferatio
n of PC14PE6 or human dermal microvascular endothelial cells, i.v. injectio
n 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 7
87 significantly reduced the formation of PE but not the number of lung les
ions, 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 PC1
4PE6 cells in vivo. These findings indicate that PTK 787 reduced PE formati
on mainly by inhibiting vascular permeability, suggesting that this VEGF/VP
F receptor tyrosine kinase inhibitor could be useful for the control of mal
ignant PE.