title: Oncolytic vaccinia virus as a vector for therapeutic sodium iodide symporter gene therapy in prostate cancer.
abstract: Oncolytic strains of vaccinia virus are currently in clinical development with clear evidence of safety and promising signs of efficacy. Addition of therapeutic genes to the viral genome may increase the therapeutic efficacy of vaccinia. We evaluated the therapeutic potential of vaccinia virus expressing the sodium iodide symporter (NIS) in prostate cancer models, combining oncolysis, external beam radiotherapy and NIS-mediated radioiodide therapy. The NIS-expressing vaccinia virus (VV-NIS), GLV-1h153, was tested in in vitro analyzes of viral cell killing, combination with radiotherapy, NIS expression, cellular radioiodide uptake and apoptotic cell death in PC3, DU145, LNCaP and WPMY-1 human prostate cell lines. In vivo experiments were carried out in PC3 xenografts in CD1 nude mice to assess NIS expression and tumor radioiodide uptake. In addition, the therapeutic benefit of radioiodide treatment in combination with viral oncolysis and external beam radiotherapy was measured. In vitro viral cell killing of prostate cancers was dose- and time-dependent and was through apoptotic mechanisms. Importantly, combined virus therapy and iodizing radiation did not adversely affect oncolysis. NIS gene expression in infected cells was functional and mediated uptake of radioiodide both in vitro and in vivo. Therapy experiments with both xenograft and immunocompetent Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mouse models showed that the addition of radioiodide to VV-NIS-infected tumors was more effective than each single-agent therapy, restricting tumor growth and increasing survival. In conclusion, VV-NIS is effective in prostate cancer models. This treatment modality would be an attractive complement to existing clinical radiotherapy practice.
authors.affiliation: Divisions of Cancer Biology and Radiotherapy and Imaging, The Institute of Cancer Research, Chester Beatty Labs, London, UK.
authors.forename: D C
authors.initials: DC
authors.lastname: Mansfield
authors.affiliation: Divisions of Cancer Biology and Radiotherapy and Imaging, The Institute of Cancer Research, Chester Beatty Labs, London, UK.
authors.forename: J N
authors.initials: JN
authors.lastname: Kyula
authors.affiliation: Divisions of Cancer Biology and Radiotherapy and Imaging, The Institute of Cancer Research, Chester Beatty Labs, London, UK.
authors.forename: N
authors.initials: N
authors.lastname: Rosenfelder
authors.affiliation: Divisions of Cancer Biology and Radiotherapy and Imaging, The Institute of Cancer Research, Chester Beatty Labs, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Chao-Chu
authors.affiliation: Divisions of Cancer Biology and Radiotherapy and Imaging, The Institute of Cancer Research, Chester Beatty Labs, London, UK.
authors.forename: G
authors.initials: G
authors.lastname: Kramer-Marek
authors.affiliation: Divisions of Cancer Biology and Radiotherapy and Imaging, The Institute of Cancer Research, Chester Beatty Labs, London, UK.
authors.forename: A A
authors.initials: AA
authors.lastname: Khan
authors.affiliation: Divisions of Cancer Biology and Radiotherapy and Imaging, The Institute of Cancer Research, Chester Beatty Labs, London, UK.
authors.forename: V
authors.initials: V
authors.lastname: Roulstone
authors.affiliation: Divisions of Cancer Biology and Radiotherapy and Imaging, The Institute of Cancer Research, Chester Beatty Labs, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: McLaughlin
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, St James's University Hospital, Leeds, UK.
authors.forename: A A
authors.initials: AA
authors.lastname: Melcher
authors.affiliation: Molecular Medicine Program, Mayo Clinic, Rochester, MN, USA.
authors.forename: R G
authors.initials: RG
authors.lastname: Vile
authors.affiliation: Postgraduate Medical School, The University of Surrey, Guildford, UK.
authors.forename: H S
authors.initials: HS
authors.lastname: Pandha
authors.affiliation: Divisions of Cancer Biology and Radiotherapy and Imaging, The Institute of Cancer Research, Chester Beatty Labs, London, UK.|The Royal Marsden Hospital, London, UK.|University of Melbourne and Monash University, Victoria, Australia.
authors.forename: V
authors.initials: V
authors.lastname: Khoo
authors.affiliation: Divisions of Cancer Biology and Radiotherapy and Imaging, The Institute of Cancer Research, Chester Beatty Labs, London, UK.|The Royal Marsden Hospital, London, UK.
authors.forename: K J
authors.initials: KJ
authors.lastname: Harrington
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D011897:Random Allocation; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014616:Vaccinia virus / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000099209:Sodium-Iodide Symporters
chemical_list: D027981:Symporters; D000099209:Sodium-Iodide Symporters
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