INHIBITION OF TUMOR-GROWTH AND MICROVASCULAR ANGIOGENESIS BY THE POTENT ANGIOGENESIS INHIBITOR, TNP-470, IN RATS

The antiangiogenic effects of TNP-470 on the neovascularization of tum ors were studied by examining ultrastructural alterations in the vascu lature and interstitial fluid pressure (IPP) of tumors. Wistar rats we re first inoculated subcutaneously (s.c.) with the Walker 256 carcinos arcoma cell line, then either vehicle medium or TNP-470, 30mg/kg, was injected s.c. on day 1. A tumor growth assay, the necrotic area, and t he IFP in the tumor were all measured on day 12. The antiangiogenic ef fects of TNP-470 were studied by scanning electron microscopic images of tumor vascular casts. TNP-470 was observed to inhibit tumor growth and increase the necrotic area significantly. In the TNP-470-treated g roup, the IFP in the superficial layer, defined as 2-3mm from the tumo r capsule, and in the deep layer, defined as 8-10mm from the tumor cap sule, were significantly higher than the corresponding values in the c ontrol. Moreover, vascular casts showed a significant reduction in the budding of sprouts in the superficial layer, and a decrease in the ma ximum diameter of the tumor vessels in the deep layer. It is possible that the higher IFP in the TNP-470-treated tumors might have prevented tumor vessel dilation. The findings of this study demonstrated that T NP-470 inhibited the budding of tumor vessel sprouts, and increased th e IFP. These processes seem to act synergistically to suppress tumor a ngiogenesis.