Sequence‐Specific Antiproliferative Effects of Antisense and End‐Capping‐Modified Antisense Oligodeoxynucleotides Targeted against the 5′‐Terminus of Basic‐Fibroblast‐Growth‐Factor mRNA in Coronary Smooth Muscle Cells

Basic fibroblast growth factor (bFGF), a potent mitogen for arterial smooth muscle cells, has been shown to play a fundamental role in the pathogenesis of arteriosclerosis and restenosis by stimulating the proliferation of vascular smooth muscle cells. We found that partially phosphorothioate‐modified 15‐residue antisense oligodeoxynucleotides complementary to bFGF mRNA at 0.1–2.0 μM block growth and division of cultured human and bovine coronary smooth muscle cells in a dose‐dependent manner. The effect is sequence specific at low (0.1–0.5 μM) nontoxic concentrations. It is associated with inhibition of expression of pericellular and intracellular bFGF, with a decreased de novo synthesis of bFGF and is partly reversible by the addition of exogenous (recombinant) bFGF. The antisense effect lasts 48–72 h and diminishes thereafter. If the antisense oligodeoxynucleotide medium is replaced by an oligo‐nucleotide‐free medium after 24 h, the [ 3 H]thymidine incorporation rate returns to control levels. Under the same conditions, the corresponding sense oligodeoxynucleotide exerts negligible nonspecific inhibitory actions. The antiproliferative potency of the 15‐residue antisense oligodeoxynucleotide is markedly enhanced by adding 3–4 nonbase‐pairing guanosine residues at the 5′‐ and 3′‐termini of the 15‐residue antisense oligonucleotide. The data implicate bFGF in the process of smooth muscle cell proliferation and an effective and specific antiproliferative potency of bFGF‐specific antisense oligonucleotides. The results point to possible new therapeutic strategies for the use of antisense methodology in the suppression of post‐angioplasty restenosis.