Phosphorothioate Oligodeoxynucleotide Inhibition of Restenosis.

Abstract

Antisense therapy with phosphorothioate oligodeoxynucleotides (PS oligos) has emerged as a potentially useful strategy for inhibiting angioplasty restenosis. Several groups have reported that PS oligos inhibit in vitro vascular smooth muscle cell (SMC) proliferation as well as in vivo neointimal formation after rat carotid artery balloon injury. More recent studies have revealed the presence of a PS oligo G-quartet inhibitory effect, reflecting binding of oligonucleotides to cellular proteins, which is distinct from a hybridization-dependent antisense effect. Studies with the 28-mer phosphorothioate cytidine homopolymer S-dC28 have demonstrated the presence of a non-G-quartet, non-sequence-specific inhibitory effect on SMC proliferation and migration in vitro and neointimal hyperplasia after rat carotid balloon injury in vivo. These effects are the result, in part, of the avid binding of the polyanion PS oligos to heparin-binding growth factors, such as platelet-derived growth factor (PDGF) and basic fibroblast growth factor. Moreover, S-dC28 attenuates PDGF-induced SMC tissue plasminogen activator antigen levels without affecting SMC plasminogen activator inhibitor-1 levels, thereby suggesting a PS oligo net antifibrinolytic effect that would impede SMC migration. Therefore, the further development of these drugs to inhibit angioplasty restenosis must consider the hybridization-specific antisense effects, the non-G-quartet inhibitory effects, and the non-G-quartet, non-sequence-specific inhibitory effects of the pleiotropic PS oligos.