A COMPARISON OF GUANOSINE-QUARTET INHIBITORY EFFECTS VERSUS CYTIDINE HOMOPOLYMER INHIBITORY EFFECTS ON RAT NEOINTIMAL FORMATION

Phosphorothioate oligodeoxynucleotides (PS oligos) manifest antisense and G-quartet aptameric inhibitory effects on vascular smooth muscle c ell (SMC) proliferation. PS oligo cytidine homopolymers also have nons equence-specific, non-G-quartet inhibitory effects on in vitro and in vivo SMC proliferation, In this study, we compared the effects of S-dC 18 and S-dC28, 18-mer and 28-mer cytidine homopolymers, respectively, which lack guanosines, with those of ZK10, a G-tetrad forming compound , on in vitro SMC proliferation and in vivo neointimal formation. ZK10 significantly inhibited in vitro human aortic SMC proliferation. At t he same molar concentration, ZK10 had significantly greater inhibitory potency on SMC proliferation than either S-dC18, S-dC28, or 7DG-ZK10, which is a modified ZK10 with ten 7-deaza guanosine substitutions. ZK 10 was significantly more potent than S-dC18 and S-dC28 in inhibiting PDGF-induced in vitro SMC migration. S-dC18, S-dC28, and ZK10 treatmen t significantly reduced the intima/media area ratio after rat carotid artery balloon injury compared with the values of the control groups. ZK10 was a more potent inhibitor of neointimal formation than the same chain length S-dC18, ZK10 formed higher-order structures, as shown on gel electrophoresis, in contrast to S-dC28 and 7DG-ZK10, Therefore, t he 18-mer ZK10 has comparable in vivo SMC inhibitory effects to the 28 -mer S-dC28, a fact that may have ramifications for the development of optimal PS oligos to inhibit angioplasty restenosis.