Interaction of angiogenesis inhibitor TNP-470 with basic fibroblast growthfactor receptors

TNP-470 is a synthetic analogue of fumagillin that acts as a potent angioge nesis inhibitor. Recently, our laboratory demonstrated that systemic admini stration of TNP-470 (5.0 mg/kg) decreased the rate of cutaneous wound heali ng by greater than 20%. In this study, we tested the hypothesis that TNP-47 0 interferes with the wound repair-stimulating action of basic fibroblast g rowth factor (bFGF) by competing with endogenous bFGF for its binding sites on the receptor protein, The influence of TNP-470 was examined ill vitro i n a ligand competition assay of high- and low-affinity receptor binding to I-125-bFGF in NIH/3T3 cells. Results demonstrated that recognition of I-125 -bFGF by low-affinity growth factor binding sites was significantly decreas ed (P < 0.01) in the presence of TNP-470. However, TNP-470 inhibition of ra diolabeled bFGF binding to high-affinity sites was not significantly affect ed (P = 0.07). In view of recent studies demonstrating that the low-affinit y receptors of bFGF were heparan sulfate proteoglycans, we suggest that the influence of TNP-470 on diminished wound healing is due to its direct reco gnition by these molecules. (C) 2000 Academic Press.