title: Efficient delivery of angiostatin K1-5 into tumors following insertion of an NGR peptide into adenovirus capsid.
abstract: Adenovirus (Ad)-mediated delivery of anti-angiogenic molecules into tumors constitutes an appealing approach for growth inhibition. However, lack of expression on tumors of Ad receptors leads to weak tumor transduction. Therefore, to provide Ad with a new entry pathway into tumors, an NGR peptide was inserted into either fiber (AdFNGR) or hexon (AdHNGR) capsid proteins. This strategy provided Ad with a very efficient entry pathway in both endothelial cells and tumor cells, with the highest efficacy observed for AdHNGR. Using pharmacological, biochemical and genetic approaches, AdHNGR and AdFNGR were shown to bind not only to CD13 receptor, but also to alphavbeta3 integrins. Both vectors were efficient tools to deliver angiostatin K1-5 cDNA into endothelial cells, thus leading to a dramatic inhibition of their proliferation and increased cell death. Although AdHNGR and Adwt were found to display similar gene transduction efficacy in Lewis lung carcinoma (LLC), pseudotyping AdHNGR with an Ad3-fiber unmasked the ability of NGR-peptide to target these tumors. As a result, delivery of angiostatin K1-5 cDNA into highly aggressive tumors translated into a stronger inhibition of their growth. Altogether, our results suggest that NGR-bearing Ad are valuable tools to realize the potential of this anti-angiogenic approach to anti-tumor therapy.
authors.affiliation: CNRS UMR 8121, Vectorologie et Transfert de Gènes, Institut Gustave Roussy, Villejuif Cedex, France.
authors.forename: B
authors.initials: B
authors.lastname: Jullienne
authors.forename: F
authors.initials: F
authors.lastname: Vigant
authors.forename: E
authors.initials: E
authors.lastname: Muth
authors.forename: R
authors.initials: R
authors.lastname: Chaligné
authors.forename: C
authors.initials: C
authors.lastname: Bouquet
authors.forename: S
authors.initials: S
authors.lastname: Giraudier
authors.forename: M
authors.initials: M
authors.lastname: Perricaudet
authors.forename: K
authors.initials: K
authors.lastname: Benihoud
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D043168:Angiostatins / Q000627:therapeutic use*; D000818:Animals; D018826:CD13 Antigens; D002213:Capsid; D018827:Carcinoma, Lewis Lung; D045744:Cell Line, Tumor; D050822:Cytokine Receptor gp130; D042783:Endothelial Cells; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000628:therapy*; D009842:Oligopeptides; D014161:Transduction, Genetic
chemical_list: C526428:NGR peptide; D009842:Oligopeptides; D050822:Cytokine Receptor gp130; D043168:Angiostatins; D018826:CD13 Antigens