Tyrphostins, inhibitors of protein tyrosine kinase, in restenosis

Accelerated proliferative response of smooth muscle cells (SMC) to vessel 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 involved in multiple steps of signal transduction of SMC growth factors. It is essential for normal cell proliferation, and greatly amplified in proliferative disorders. Thus, blocking the activity of tyrosine kinases may provide a unique and useful strategy for the treatment of syndromes involving accelerated proliferation of vascular SMC. It was shown that a series of low molecular weight PTK inhibitors, termed tyrphostins inhibit PDGF-dependent DNA synthesis and cell growth in vitro and in vivo, and that this occurs in large part by inhibition of PDGF receptor autophosphorilation. This paper reviews the data on tyrphostins activity in cell cultures of vascular SMC, in in vivo models of restenosis, and describes the potential therapeutic approach of tyrphostin delivery in restenosis.