Interaction of angiogenesis inhibitor TNP-470 with basic fibroblast growth factor receptors.
TNP-470 is a synthetic analogue of fumagillin that acts as a potent angiogenesis inhibitor. Recently, our laboratory demonstrated that systemic administration of TNP-470 (5.0 mg/kg) decreased the rate of cutaneous wound healing by greater than 20%. In this study, we tested the hypothesis that TNP-470 interferes with the wound repair-stimulating action of basic fibroblast growth factor (bFGF) by competing with endogenous bFGF for its binding sites on the receptor protein. The influence of TNP-470 was examined in vitro in a ligand competition assay of high- and low-affinity receptor binding to (125)I-bFGF in NIH/3T3 cells. Results demonstrated that recognition of (125)I-bFGF by low-affinity growth factor binding sites was significantly decreased (P < 0.01) in the presence of TNP-470. However, TNP-470 inhibition of radiolabeled bFGF binding to high-affinity sites was not significantly affected (P = 0.07). In view of recent studies demonstrating that the low-affinity receptors of bFGF were heparan sulfate proteoglycans, we suggest that the influence of TNP-470 on diminished wound healing is due to its direct recognition by these molecules.
Bond
S J
SJ
Department of Surgery, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA. sjbond01@athena.louisville.edu
Klein
S A
SA
Anderson
G L
GL
Wittliff
J L
JL
D016475:3T3 Cells; D020533:Angiogenesis Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D003510:Cyclohexanes; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D007457:Iodine Radioisotopes; D051379:Mice; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry / Q000378:metabolism*; D012717:Sesquiterpenes / Q000378:metabolism / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology
D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D007457:Iodine Radioisotopes; D017468:Receptors, Fibroblast Growth Factor; D012717:Sesquiterpenes; D016222:Fibroblast Growth Factor 2; D000077609:O-(Chloroacetylcarbamoyl)fumagillol