(Circulation. 1999;99:3292-3299.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Restenosis Following Angioplasty in the Swine Coronary Artery Is Inhibited By an Orally Active PDGF-Receptor Tyrosine Kinase Inhibitor, RPR101511A
From the Departments of Cardiovascular Biology (G.B., T.W., R.L., D.A., L.B., S.N., H.G., J.B., C.K., L.M., M.P., C.D.), Medicinal Chemistry (M.M., A.S., C.L., P.P.), and Laboratory Animal Resources (B.O.), Rhone-Poulenc Rorer, Collegeville, Pa, and Drug Metabolism (K.P.), Rhone-Poulenc Rorer, Dagenham, Essex, UK.
Background—Platelet-derived growth factor (PDGF), a purported mediator of arterial response to injury, stimulates proliferation, chemotaxis, and matrix production by activation of its membrane receptor tyrosine kinase. Because these activities underlie restenosis, inhibition of the PDGF-receptor tyrosine kinase (PDGFr-TK) is postulated to decrease restenosis.
Methods and Results—RPR101511A is a novel compound which selectively and potently inhibits the cell-free and in situ PDGFr-TK and PDGFr-dependent proliferation and chemotaxis in vascular smooth muscle cells (VSMC). To evaluate the effect of RPR101511A (30 mg · kg-1 · d-1 BID for 28 days following PTCA) on coronary restenosis, PTCA was performed in hypercholesterolemic minipigs whose left anterior descending (LAD) coronary artery had been injured by overdilation and denudation, yielding a previously existing lesion. Angiographically determined prePTCA minimal lumen diameters (MLD) were similar in vehicle and RPR101511A-treated pigs (1.98±0.09 versus 2.01±0.08 mm) and increased to the same extent in the 2 groups following successful PTCA (2.30±0.06 versus 2.52±0.13). At termination, there was an average 50% loss of gain in the vehicle-treated group but no loss of gain with RPR101511A (2.16±0.05 versus 2.59±0.11, P<0.001). Morphometric analysis of the LAD showed that RPR101511A caused a significant decrease in total intimal/medial ratio (0.96±0.58 versus 0.67±0.09, P<0.05).
Conclusions—RPR101511A, which acts by inhibition of the PDGFr-TK, completely prevented angiographic loss of gain following PTCA and significantly reduced histological intimal hyperplasia.
Key Words: angioplasty • restenosis • platelet-derived factors
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