Inhibition of tyrosine kinase activity by sugen 5416 inhibits fibrin dependent angiogenesis
Fibrin provides the provisional matrix that aids wound healing and angiogenesis. In this study we used a novel in vivo method (Z-Chambers) to study fibrin dependent angiogenesis and tested whether inhibition of tyrosine kinase would alter tumor angiogenesis and wound healing. Chambers were constructed from a plexiglass ring and Fibrin was formed by addition of thrombin in the chamber. The chambers had either fibrin alone (fibrin Z-chambers to study wound healing) or tumor cells with fibrin (tumor Z-chambers to study tumor growth and angiogenesis}. The dorsal subcutaneous tissue of the rat and the chambers were harvested at day 12 post implantation. Rats were administered SUGEN 5416 (an inhibitor of VEGF receptor Flk) starting 2 days prior to implanting chambers at 20 mg/kg IP. The body weight loss for both controls and treatment animals was within 5% of baseline. The fibrin Z-Chambers in treated animals developed significantly less granulation tissue (p=0.0076) and average microvessel density (p=0.0009) and had an overall delayed normal wound healing response. The tumor Z-chambers were implanted with rat mammary carcinoma R3230. We also observed significantly decreased tumor growth (p<0.0001) but the average microvessel density in the tumor mass that did develop was no different than controls. In conclusion, we have developed a novel method to study how fibrin can promote tumor angiogenesis and wound healing in a highly reproducible and technically easy system. In addition, the activity of the Tyrosine kinases appears to be important for the formation of blood vessels that are associated with tumor angiogenesis and normal wound healing.