title: Tumour-specific triple-regulated oncolytic herpes virus to target glioma.
abstract: Oncolytic herpes simplex virus type 1 (oHSV-1) therapy is an emerging treatment modality that selectively destroys cancer. Here we report use of a glioma specific HSV-1 amplicon virus (SU4-124 HSV-1) to selectively target tumour cells. To achieve transcriptional regulation of the SU4-124 HSV-1 virus, the promoter for the essential HSV-1 gene ICP4 was replaced with a tumour specific survivin promoter. Translational regulation was achieved by incorporating 5 copies of microRNA 124 target sequences into the 3'UTR of the ICP4 gene. Additionally, a 5'UTR of rat fibroblast growth factor -2 was added in front of the viral ICP4 gene open reading frame. Our results confirmed enhanced expression of survivin and eIF4E in different glioma cells and increased micro-RNA124 expression in normal human and mouse brain tissue. SU4-124 HSV-1 had an increased ICP4 expression and virus replication in different glioma cells compared to normal neuronal cells. SU4-124 HSV-1 exerted a strong antitumour effect against a panel of glioma cell lines. Intracranial injection of SU4-124 HSV-1 did not reveal any sign of toxicity on day 15 after the injection. Moreover, a significantly enhanced antitumour effect with the intratumourally injected SU4-124 HSV-1 virus was demonstrated in mice bearing human glioma U87 tumours, whereas viral DNA was almost undetectable in normal organs. Our study indicates that incorporation of multiple cancer-specific regulators in an HSV-1 system significantly enhances both cancer specificity and oncolytic activity.
authors.affiliation: Experimental Medicine Program, Department of Medicine, University of British Columbia, Vancouver, Canada.|Department of Surgery, University of British Columbia, Vancouver, Canada.|Brain Research Centre, University of British Columbia, Vancouver, Canada.
authors.forename: Zahid M
authors.initials: ZM
authors.lastname: Delwar
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, Canada.|Brain Research Centre, University of British Columbia, Vancouver, Canada.
authors.forename: Guoyu
authors.initials: G
authors.lastname: Liu
authors.affiliation: Brain Research Centre, University of British Columbia, Vancouver, Canada.|Department of Biology, University of British Columbia, Vancouver, Canada.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Kuo
authors.affiliation: Brain Research Centre, University of British Columbia, Vancouver, Canada.
authors.forename: Cleo
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, Canada.|Brain Research Centre, University of British Columbia, Vancouver, Canada.
authors.forename: Luke
authors.initials: L
authors.lastname: Bu
authors.affiliation: Department of Urology, University of British Columbia, Vancouver, Canada.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Rennie
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, Canada.|Brain Research Centre, University of British Columbia, Vancouver, Canada.
authors.forename: William W
authors.initials: WW
authors.lastname: Jia
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D005910:Glioma / Q000235:genetics / Q000628:therapy* / Q000821:virology; D057809:HEK293 Cells; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000502:physiology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D051379:Mice; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics* / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D000077022:Survivin; D047368:Tumor Burden / Q000235:genetics; D014709:Vero Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; C107489:BIRC5 protein, human; D017874:Immediate-Early Proteins; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; C048925:herpes simplex virus, type 1 protein ICP4; D016222:Fibroblast Growth Factor 2
keywords: 5’UTR; glioma; microRNA; oncolytic herpes virus; survivin