title: Apoptosis mediated by lentiviral TRAIL transfer involves transduction-dependent and -independent effects.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent, which selectively induces apoptosis in many transformed cells without apparent toxic side effects in normal tissue. We recently described the construction and characterization of a lentiviral vector for expression of TRAIL. In this report, we evaluate its suitability for therapeutic application. In vitro, we observed specific induction of apoptosis upon transduction in human lung cancer cells. Cell death was partially dependent on successful integration and TRAIL expression by the vectors, but was to some extent mediated by protein carryover, as we found TRAIL protein associated with virus particles. Transduction of subcutaneously growing lung tumors on nude mice with lentiviral TRAIL mediated a transient suppression of tumor growth. Analysis of tumor sections revealed that transduction efficiency of lentiviral control vector but not of lentiviral TRAIL vector was high. This was because of the direct cytotoxic activity of recombinant TRAIL present in viral particles, which prevented efficient tumor transduction. These data therefore suggest that enveloped viral vectors constitutively expressing TRAIL are well suited for ex vivo applications, such as the transduction of tumor-homing cells, but may have a lower effect when used directly for the transduction of tumor cells in vivo.
authors.affiliation: Research Group Molecular OncoSurgery, Heidelberg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Wenger
authors.forename: J
authors.initials: J
authors.lastname: Mattern
authors.forename: T L
authors.initials: TL
authors.lastname: Haas
authors.forename: M R
authors.initials: MR
authors.lastname: Sprick
authors.forename: H
authors.initials: H
authors.lastname: Walczak
authors.forename: K-M
authors.initials: KM
authors.lastname: Debatin
authors.forename: M W
authors.initials: MW
authors.lastname: Büchler
authors.forename: I
authors.initials: I
authors.lastname: Herr
mesh_terms: D000818:Animals; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002478:Cells, Cultured; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008024:Ligands; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014771:Virion / Q000378:metabolism
chemical_list: D008024:Ligands; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha