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Combretastatin-A4 disodium phosphate (CA4DP) is a vascular-disruptive agent that causes an abrupt decrease in tumor blood flow. The direct actions of CA4DP include increases in vascular permeability and destabilization of the endothelial cytoskeleton, which are thought to contribute to occlusion of the tumor vasculature. It has been proposed that increased permeability causes a transient increase in interstitial fluid pressure (IFP), which in turn could collapse intratumoral blood vessels. We examined the immediate effects of CA4DP on tumor IFP in C3H mammary carcinoma. Mice were treated with 100 mg/kg CA4DP by intraperitoneal injection. Tumor perfusion was recorded by laser Doppler flowmetry at separate time points, and IFP was recorded continuously by the wick-in-needle method. In this study, we found that CA4DP treatment resulted in a rapid reduction in tumor perfusion, followed by a decrease in IFP; no increases in IFP were observed. This suggests that CA4DP-induced reductions in tumor perfusion are not dependent on increases in IFP. [ABSTRACT FROM AUTHOR]

Angiopoietins (Ang) are involved in the remodeling, maturation, and stabilization of the vascular network. Ang-4 was discovered more recently; thus, its effect on angiogenesis and its interplay with other angiogenic factors have not been equivocally established. The role of Ang-4 in angiogenesis was tested in Matrigel chambers implanted into the subcutaneous space of nude mice. Ang-4 inhibited the angiogenic response of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and GLC19 tumor cells. In Matrigel chambers with Ang-4--transfected cells, the mean response was significantly lower than that of mock cells. Subcutaneous tumor interstitial fluid pressure (IFP) was significantly lower in Ang-4--transfected GLC19 tumors than in mock-transfected tumors. IFP reduction in Ang-4--transfected tumors was comparable to the reduction seen after bevacizumab treatment. In vitro, we examined the effect of recombinant Ang-4 on endothelial cell migration in Boyden chambers. Human umbilical vein endothelial cell (HUVEC) migration induced by bFGF and VEGF was inhibited by Ang-4 to control levels. In conclusion, we show that rhAng-4, as well as transfection with Ang-4, inhibits angiogenesis induced by GLC19 tumor cells and that Ang-4 expression reduces elevated tumor IFP. In addition, we demonstrate that rhAng-4 inhibits HUVEC migration and growth factor--induced angiogenesis. [ABSTRACT FROM AUTHOR]