Inhibition of malignant ascites and growth of human ovarian carcinoma by oral administration of a potent inhibitor of the vascular endothelial growthfactor receptor tyrosine kinases

We determined whether inhibition of the catalytic tyrosine kinase activity of the receptors for vascular endothelial growth factor/vascular permeabili ty factor (VEGF/VPF) inhibits the formation of malignant ascites and the pr ogressive growth of human ovarian carcinoma cells implanted into the perito neal cavity of nude mice. The novel protein tyrosine inhibitor PTK 787 was evaluated in two models of human ovarian cancer: Hey-A8 cells, which expres s low levels of VEGF/VPF and grow as solid tumor foci on the surface of per itoneal organs, and SKOV3 i.p.l cells, which express high levels of VEGF/VP F and grow as solid peritoneal tumors and ascites. Treatment of nude mice b y daily oral administration of 50 mg/kg PTK 787 was not effective against H ey-A8 tumors. In sharp contrast, it significantly inhibited growth of SKOV3 i.p.l cells and formation of ascites, significantly increasing survival of mice with the implants. Tumor-induced vascular hyperpermeability in the pe ritoneum of tumor-bearing mice was inhibited by PTK 787, which accounted fo r its inhibition of ascites formation. Our results suggest that blockade of the VEGF/VPF receptor may be an efficient strategy to inhibit formation of malignant ascites and growth of VEGF/VPF-dependent human ovarian carcinoma s.