INHIBITION OF PDGF RECEPTOR-BINDING AND PDGF-STIMULATED BIOLOGICAL-ACTIVITY IN-VITRO AND OF INTIMAL LESION FORMATION IN-VIVO BY 2-BROMOMETHYL-5-CHLOROBENZENE SULFONYLPHTHALIMIDE

The proliferation of vascular smooth muscle cells (SMCs) is a key even t in the development of atherosclerotic lesions and in the restenosis of arteries after angioplasty. Polypeptide growth factors are potent S MC mitogens in vitro and are believed to be involved in SMC proliferat ion in vivo. Strong data exist linking platelet-derived growth factor (PDGF) activity to human atherosclerosis. However, no low-molecular-we ight antagonists of this growth factor have been discovered. We identi fied a compound, SCH 13929 (2-bromomethyl-5-chlorobenzene sulfonylphth alimide), which inhibits binding of I-125-PDGF BB to cell surface rece ptors with an IC50 of 0.13 mu mol/L. This compound has a lesser effect on the binding of I-125-epidermal growth factor (EGF), I-125-basic fi broblast growth factor (bFGF), or I-125-endothelin to specific cell su rface receptors. Exposure of cultured SMCs to SCH 13929 inhibits PDGF BB- and PDGF AA-stimulated DNA synthesis but not EGF- or bFGF-stimulat ed DNA synthesis. PDGF BB-stimulated SMC division is also inhibited by exposure to SCH 13929. Chemotaxis assays indicate that SCH 13929 inhi bits PDGF-stimulated directional migration and suggest that the compou nd interacts with PDGF rather than with the receptor. Oral administrat ion of SCH 13929 (100 mg/kg per day) to Sprague-Dawley rats or spontan eously hypertensive rats results in significant inhibition of lesion f ormation in the balloon catheter-deendothelialized carotid artery. The se results suggest that SCH 13929 may be a useful tool for understandi ng the role of PDGF in intimal lesion formation.