title: In vivo potentialities of EWS-Fli-1 targeted antisense oligonucleotides-nanospheres complexes.
abstract: The EWS/FLI-1 fusion gene, resulting from a t(11;22) translocation, plays a key role in the pathogenesis of Ewing sarcoma. Previously, we have shown that antisense oligonucleotides designed against EWS-Fli-1 inhibited tumor growth in nude mice provided they were delivered intratumorally by nanocapsules or by CTAB-coated nanospheres. In this study, we have used two types of nanospheres (designated as type 1 and type 2 nanospheres) stabilized with chitosan for both intratumoral and systemic administration of oligonucleotides. Inhibition of the tumor growth in vivo was found to be dependent on the carrier type as well as on antisense oligonucleotide modification. Indeed, whereas both types of nanospheres were efficient in reducing tumor growth after intratumoral injection, we have obtained only with type 2 nanospheres an antitumoral effect after intravenous injection in a preliminary experiment. Additionally, the anticancer efficacy of a localized modification of the EWS-Fli-1 phosphodiester/phosphorothioate chimeric antisense oligonucleotide was demonstrated. In cell culture the oligonucleotides inhibit cell growth by their antisense activity. Further investigations are needed in vivo to learn the mechanism of action of the complexes.
authors.affiliation: Bioalliance Pharma SA, Paris 75015, France.
authors.forename: Andrei
authors.initials: A
authors.lastname: Maksimenko
authors.forename: Valerie
authors.initials: V
authors.lastname: Polard
authors.forename: Marie
authors.initials: M
authors.lastname: Villemeur
authors.forename: Hind
authors.initials: H
authors.lastname: Elhamess
authors.forename: Patrick
authors.initials: P
authors.lastname: Couvreur
authors.forename: Jean-Remi
authors.initials: JR
authors.lastname: Bertrand
authors.forename: Malam
authors.initials: M
authors.lastname: Aboubakar
authors.forename: Marina
authors.initials: M
authors.lastname: Gottikh
authors.forename: Claude
authors.initials: C
authors.lastname: Malvy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D048271:Chitosan / Q000737:chemistry; D018899:CpG Islands; D019175:DNA Methylation; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D041681:NIH 3T3 Cells; D043942:Nanotubes / Q000737:chemistry*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000628:therapy*; D016376:Oligonucleotides, Antisense / Q000737:chemistry*; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics* / Q000378:metabolism*; D034802:RNA-Binding Protein EWS / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; C106031:EWS-FLI fusion protein; C497426:Fli1 protein, mouse; D016376:Oligonucleotides, Antisense; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D048271:Chitosan