Phosphorothioate oligodeoxynucleotides inhibit basic fibroblast growth factor-induced angiogenesis in vitro and in vivo.
Angiogenesis is regulated by heparin-binding growth factors, such as basic fibroblast growth factor (bFGF). We investigated the effects of phosphorothioate-mediated oligodeoxynucleotides (PS-ODN) on bFGF-induced angiogenesis. Because PS-ODN are polyanions, they can also bind many heparin-binding proteins. On a basement matrix using a Matrigel matrix, we observed <50% tube formation by human umbilical endothelial cells with 10 microM bFGF, vascular endothelial growth factor, or nuclear factor-kappaB (NF-kappaB) antisense and sense PS-ODN, while phosphodiester oligodeoxynucleotides (PO-ODNs) were not affected. The PS-ODN, but not the PO-ODN, inhibited the bFGF-induced rabbit corneal neovascularization. In albino rats, the NF-kappaB antisense PS-ODN showed a low rescue score for bFGF-dependent photoreceptor rescue because of their degradation by constant light exposure. However, antisense PS-ODN active against bFGF inhibited angiogenesis more strongly than did the antisense NF-kappaB PS-ODN. Because of the important role bFGF plays in angiogenesis, some PS-ODN may serve as potent antiangiogenic compounds that act through a combination of polyanionic phosphorothioate effects and a sequence-specific antisense mechanism.
Kitajima
I
I
Department of Laboratory and Molecular Medicine, Kagoshima University, Faculty of Medicine, Japan.
Unoki
K
K
Maruyama
I
I
D000818:Animals; D001485:Basement Membrane / Q000098:blood supply; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003315:Cornea / Q000098:blood supply; D004730:Endothelium, Vascular / Q000166:cytology; D016222:Fibroblast Growth Factor 2 / Q000187:drug effects / Q000235:genetics* / Q000494:pharmacology; D006801:Humans; D016328:NF-kappa B / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects / Q000528:radiation effects; D011817:Rabbits; D051381:Rats; D013873:Thionucleotides / Q000494:pharmacology*
D016328:NF-kappa B; D020319:Oligodeoxyribonucleotides, Antisense; D013873:Thionucleotides; D016222:Fibroblast Growth Factor 2