title: Stent-induced restenosis in the swine coronary artery is inhibited by a platelet-derived growth factor receptor tyrosine kinase inhibitor, TKI963.
abstract: Activities of vascular smooth muscle cells (SMCs) such as proliferation, migration, and matrix production contribute to restenosis following clinical interventions of angioplasty and stent placement. Because activation of platelet-derived growth factor (PDGF)-receptor tyrosine kinase (PDGFr-TK) influences these processes and promotes restenosis, TKI963, an inhibitor of the PDGFr-TK was discovered, and its efficacy was evaluated in blocking stent-induced restenosis as analyzed by intravascular ultrasound (IVUS). TKI963, a low-molecular-weight compound, inhibited the cell-free PDGFbetar-TK with a K(i) value of 56 +/- 14 nM. TKI963 also inhibited PDGF-dependent events in human aortic SMCs (e.g., in situ PDGFr autophosphorylation, mitogenesis, chemotaxis, and collagen production with median inhibitory concentration values of approximately 300 nM) without affecting the activity of a series of membrane receptor tyrosine kinases and intracellular serine/threonine kinases. In vivo, stent-induced restenosis in the swine coronary artery was reduced by oral administration of TKI963 (1.25, 2.5, and 5 mg/kg BID, for 28 days). Late lumen cross-sectional area (CSA) loss, plaque CSA growth, and plaque volume in the stent determined by IVUS were dose-relatedly decreased (33-62% at 1.25 mg/kg BID to 66-92% at 5 mg/kg BID, depending on the parameter) compared with controls. TKI963 treatment of </=1 week following stent placement had no effect on the prevention of restenosis. TKI963, a selective, orally bioavailable inhibitor of the PDGFr-TK, dose-relatedly reduced stent-induced restenosis and did so by inhibiting PDGF-dependent activities that occur as late events following stent placement.
authors.affiliation: Aventis Pharmaceuticals, Inc., Collegeville, Pennsylvania, USA. gebilder@hotmail.com
authors.forename: Glenda
authors.initials: G
authors.lastname: Bilder
authors.forename: Dilip
authors.initials: D
authors.lastname: Amin
authors.forename: Lisa
authors.initials: L
authors.lastname: Morgan
authors.forename: Matthew
authors.initials: M
authors.lastname: McVey
authors.forename: Saul
authors.initials: S
authors.lastname: Needle
authors.forename: Helen
authors.initials: H
authors.lastname: Galczenski
authors.forename: Robert
authors.initials: R
authors.lastname: Leadley
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.forename: Michael
authors.initials: M
authors.lastname: Myers
authors.forename: Alfred
authors.initials: A
authors.lastname: Spada
authors.forename: Yongyi
authors.initials: Y
authors.lastname: Luo
authors.forename: Chandra
authors.initials: C
authors.lastname: Natajaran
authors.forename: Mark
authors.initials: M
authors.lastname: Perrone
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D003094:Collagen / Q000096:biosynthesis; D023903:Coronary Restenosis / Q000209:etiology* / Q000517:prevention & control*; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015607:Stents / Q000009:adverse effects*; D013556:Swine, Miniature
chemical_list: D011810:Quinoxalines; C483458:TKI 963; D003094:Collagen; C099852:PDGF receptor tyrosine kinase; D017479:Receptors, Platelet-Derived Growth Factor