title: A Herpesvirus saimiri-based vector expressing TRAIL induces cell death             in human carcinoma cell lines and multicellular spheroid cultures.
abstract: Herpesvirus saimiri (HVS) is capable of infecting a range of human carcinoma cell types with high efficiency and the viral genome persists as high copy number, circular, non-integrated episomes which segregate to progeny upon cell division. This allows HVS-based vectors to stably transduce a dividing cell population and provide sustained transgene expression for an extended period of time both in vitro and in vivo. Moreover, the insertion of a bacterial artificial chromosome cassette into the HVS genome simplifies the incorporation of large amounts of heterologous DNA for gene delivery. Herein we have produced a recombinant HVS-based vector containing full-length human TRAIL under the control of the α-survivin promoter, and subsequently challenged a variety of cancer cell lines with this vector. The TRAIL transgene was expressed in infected colorectal SW480 cells, causing considerable apoptosis induction. Apoptosis was also observed when several other cancer cell lines derived from different tissues were infected. Moreover, co-treatment with Jak inhibitor AG490 led to the disruption of spheroid cultures grown from the melanoma Mel888 line. These data suggest that an HVS gene therapy vector expressing TRAIL could be an effective treatment against cancer.
authors.affiliation: Institute of Molecular and Cellular Biology, Faculty of Biological                     Sciences, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Turrell
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Macnab
authors.forename: Ailsa
authors.initials: A
authors.lastname: Rose
authors.forename: Alan A
authors.initials: AA
authors.lastname: Melcher
authors.forename: Adrian
authors.initials: A
authors.lastname: Whitehouse
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D015316:Genetic Therapy; D005822:Genetic Vectors; D057809:HEK293 Cells; D006567:Herpesvirus 2, Saimiriine / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000628:therapy*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D017384:Sequence Deletion; D018874:Spheroids, Cellular; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D020169:Caspases