Stent-induced restenosis in the swine coronary artery is inhibited by a platelet-derived growth factor receptor tyrosine kinase inhibitor, TKI963.
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.
Bilder
Glenda
G
Aventis Pharmaceuticals, Inc., Collegeville, Pennsylvania, USA. gebilder@hotmail.com
Amin
Dilip
D
Morgan
Lisa
L
McVey
Matthew
M
Needle
Saul
S
Galczenski
Helen
H
Leadley
Robert
R
He
Wei
W
Myers
Michael
M
Spada
Alfred
A
Luo
Yongyi
Y
Natajaran
Chandra
C
Perrone
Mark
M
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
D011810:Quinoxalines; C483458:TKI 963; D003094:Collagen; C099852:PDGF receptor tyrosine kinase; D017479:Receptors, Platelet-Derived Growth Factor