Antisense oligonucleotides adsorbed to polyalkylcyanoacrylate nanoparticles specifically inhibit mutated Ha-ras-mediated cell proliferation and tumorigenicity in nude mice.
Ras oncogenes owe their transforming properties to single point mutations in the sequence coding for the active site of the p21 protein. These mutations lead to changes in cellular proliferation and induce tumorigenic properties. Point mutations represent a well-defined target for antisense oligonucleotides that can specifically suppress the translation of the targeted mutant mRNA. We show that the stability and cellular disponibility of antisense oligonucleotides can be markedly improved by adsorption to polyalkylcyanoacrylate nanoparticles. Nanoparticle-adsorbed antisense oligonucleotides directed to a point mutation (G-->U) in codon 12 of the Ha-ras mRNA selectively inhibited the proliferation of cells expressing the point-mutated Ha-ras gene at a concentration 100 times lower than free oligonucleotides. In addition they markedly inhibited Ha-ras-dependent tumor growth in nude mice after subcutaneous injection. These experiments show that inhibition of ras oncogenes by antisense oligonucleotides can block tumor development even though ras oncogenic activation might be an early event in tumor progression.
Schwab
G
G
Laboratoire de Biophysique, Institut National de la Santé et de la Recherche Médicale Unité 201, Centre National de la Recherche Scientifique Unité de Recherche Associée 481, Paris, France.
Chavany
C
C
Duroux
I
I
Goubin
G
G
Lebeau
J
J
Hélène
C
C
Saison-Behmoaras
T
T
D000327:Adsorption; D000818:Animals; D001483:Base Sequence; D001940:Breast; D002455:Cell Division / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D003487:Cyanoacrylates; D005091:Exons; D005260:Female; D011905:Genes, ras; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016376:Oligonucleotides, Antisense / Q000493:pharmacokinetics / Q000494:pharmacology*; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control
D003487:Cyanoacrylates; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)