Weekly Dosing With the Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor SU9518 Significantly Inhibits Arterial Stenosis

Abstract

Abstract-The platelet-derived growth factor (PDGF) ligands and their receptors have been implicated as critical regulators of the formation of arterial lesions after tissue injury. SU9518 (3[5-{5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl}-2,4-dimethyl-1H-pyrrol-3-yl]propionic acid) is a novel synthetic indolinone that potently and selectively inhibits the cellular PDGF receptor kinase and PDGF receptor-induced cell proliferation. Inhibition of PDGF receptor phosphorylation in cell-based assays occurs within 5 minutes after drug exposure and persists for Ͼ6 hours after drug removal. The pharmacokinetics indicate plasma levels that exceeded the effective concentration required to inhibit the PDGF receptor in cells for up to 8 hours or 7 days after a single oral or subcutaneous administration, respectively. In the rat balloon arterial injury-induced stenosis model, once-daily oral or once-weekly subcutaneous administration of SU9518 reduced intimal thickening of the carotid artery (ratio of neointimal to medial area,

Role of platelet-derived growth factors in physiology and medicine

“…A number of different gain-and loss-of-function experiments suggest a role for PDGF in animal models of atherosclerosis. Specifically, in different animal models of acute arterial injury by balloon catheterization, neointimal SMC accumulation was reduced by the administration of various PDGF pathway inhibitors, including neutralizing PDGF (AB) antibodies (Ferns et al 1991;Lewis et al 2001), PDGF-B aptamers (Leppänen et al 2000), PDGFR kinase inhibitors (Banai et al 1998;Yamasaki et al 2001), and PDGFR-neutralizing antibodies (Giese et al 1999;Hart et al 1999). Restenosis following angioplasty of atherosclerotic vessels in minipigs (Bilder et al 1999) and chronic cardiac transplant rejection-induced atherosclerosis in rats (Sihvola et al 1999) were also inhibited by PDGFR-blocking kinase inhibitors.…”

Gambogic Acid Induces G0/G1 Cell Cycle Arrest and Cell Migration Inhibition Via Suppressing PDGF Receptor β Tyrosine Phosphorylation and Rac1 Activity in Rat Aortic Smooth Muscle Cells

“…3 H]-thymidine was extracted by 1.0 mol/L NaOH with 500 L per well; the extracted solution was then Platelet-derived growth factor (PDGF) is known to be an important stimulator [1][2][3] . Much evidence indicates that PDGF-BB and PDGF receptor (PDGFR-)-mediated signals are particularly important for vascular remodeling and neointima formation after vascular injury [4][5][6] .…”

Counter-Regulatory Function of Protein Tyrosine Phosphatase 1B in Platelet-Derived Growth Factor– or Fibroblast Growth Factor–Induced Motility and Proliferation of Cultured Smooth Muscle Cells and in Neointima Formation

“…2 Several reports indicate that injury-induced movement of smooth muscle cells from media to intima and the proliferation of smooth muscle cells in intima are significantly reduced by pharmacological antagonists of the function or availability of PDGF or FGF2. [3][4][5][6][7] Conversely, administration of PDGF-BB or FGF2 has been reported to enhance smooth muscle cell movement from media to intima, followed by cell proliferation in vessels with minimal endothelial damage. 7,8 These studies indicate that PDGF and FGF are important mediators of neointima formation in models of vascular injury.…”