VEGF/Flk-1 interaction, a requirement for malignant ascites recurrence

Vascular endothelial growth factor (VEGF) plays an important role in the pr oduction of ascitic fluid associated with malignant tumor growth, In an exp erimental model for malignant ascites formation, mice were inoculated intra peritoneally with syngeneic mouse sarcoma tumor cells, Ascites development was not prevented by administering tumor necrosis factor (TNF) simultaneous ly with the tumor cell inoculation. When the malignant ascites was first dr ained and renewal of ascites was monitored, however, a TNF dose-dependent i nhibition of ascitic fluid accumulation was observed. Northern blot analyse s indicated transient downregulation by TNF on the expression of VEGF mRNA in tumor cells, Monoclonal antibody, (mAb) DC101 generated against the mous e VEGF receptor Flk-1 prevented the recurrence of malignant ascites in mice similar to TNF inhibition. In addition, exogenous soluble human Flt-1 used as an inhibitor of endogenous VEGF binding also inhibited ascites recurren ce, These data demonstrate that the observed inhibitory effect of TNF on re establishment of malignant ascites can be achieved equally by inhibition of the interaction of VEGF with its receptor Flk-1.