TYRPHOSTINS, INHIBITORS OF PROTEIN-TYROSINE KINASE, IN RESTENOSIS

Accelerated proliferative response of smooth muscle cells (SMC) to ves sel wall injury is the principal cause of premature coronary occlusion in patients undergoing heart transplantation, coronary artery bypass grafting, and PTCA. Protein tyrosine kinases (PTK) activity is involve d in multiple steps of signal transduction of SMC growth factors. It i s essential for normal cell proliferation, and greatly amplified in pr oliferative disorders. Thus, blocking the activity of tyrosine kinases may provide a unique and useful strategy for the treatment of syndrom es involving accelerated proliferation of vascular SMC. It was shown t hat a series of low molecular weight PTK inhibitors, termed tyrphostin s inhibit PDGF-dependent DNA synthesis and cell growth in vitro and in vivo, and that this occurs in large part by inhibition of PDGF recept or autophosphorilation. This paper reviews the data on tyrphostins act ivity in cell cultures of vascular SMC, in in vivo models of restenosi s, and describes the potential therapeutic approach of tyrphostin deli very in restenosis.