title: The potential application of a transcriptionally regulated oncolytic herpes simplex virus for human cancer therapy.
abstract: BACKGROUND
  Emerging studies have shown the potential benefit of arming oncolytic viruses with therapeutic genes. However, most of these therapeutic genes are placed under the regulation of ubiquitous viral promoters. Our goal is to generate a safer yet potent oncolytic herpes simplex virus type-1 (HSV-1) for cancer therapy.
  
  
  METHODS
  Using bacterial artificial chromosome (BAC) recombineering, a cell cycle-regulatable luciferase transgene cassette was replaced with the infected cell protein 6 (ICP6) coding region (encoded for UL39 or large subunit of ribonucleotide reductase) of the HSV-1 genome. These recombinant viruses, YE-PC8, were further tested for its proliferation-dependent luciferase gene expression.
  
  
  RESULTS
  The ability of YE-PC8 to confer proliferation-dependent transgene expression was demonstrated by injecting similar amount of viruses into the tumour-bearing region of the brain and the contralateral normal brain parenchyma of the same mouse. The results showed enhanced levels of luciferase activities in the tumour region but not in the normal brain parenchyma. Similar findings were observed in YE-PC8-infected short-term human brain patient-derived glioma cells compared with normal human astrocytes. intratumoural injection of YE-PC8 viruses resulted in 77% and 80% of tumour regression in human glioma and human hepatocellular carcinoma xenografts, respectively.
  
  
  CONCLUSIONS
  YE-PC8 viruses confer tumour selectivity in proliferating cells and may be developed further as a feasible approach to treat human cancers.
authors.affiliation: Laboratory of Cancer Gene Therapy, Cellular and Molecular Research Division, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610, Singapore.
authors.forename: L
authors.initials: L
authors.lastname: Miao
authors.affiliation: Institute of Virology, University of Zurich, Winterthurerstrasse 266a, CH-8057, Zurich, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Fraefel
authors.affiliation: Laboratory of Cancer Gene Therapy, Cellular and Molecular Research Division, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610, Singapore.
authors.forename: K C
authors.initials: KC
authors.lastname: Sia
authors.affiliation: Laboratory of Cancer Gene Therapy, Cellular and Molecular Research Division, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610, Singapore.
authors.forename: J P
authors.initials: JP
authors.lastname: Newman
authors.affiliation: Laboratory of Cancer Gene Therapy, Cellular and Molecular Research Division, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610, Singapore.
authors.forename: S A
authors.initials: SA
authors.lastname: Mohamed-Bashir
authors.affiliation: 1] Department of Neurosurgery, National Neuroscience Institute, Singapore 308433, Singapore [2] Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore 169857, Singapore.
authors.forename: W H
authors.initials: WH
authors.lastname: Ng
authors.affiliation: 1] Laboratory of Cancer Gene Therapy, Cellular and Molecular Research Division, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore 169610, Singapore [2] Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore 169857, Singapore [3] Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
authors.forename: P Y P
authors.initials: PY
authors.lastname: Lam
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000628:therapy* / Q000821:virology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000628:therapy / Q000821:virology; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005260:Female; D005910:Glioma / Q000235:genetics / Q000628:therapy* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000628:therapy / Q000821:virology; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D050130:Oncolytic Virotherapy / Q000379:methods*; D050436:Regulatory Elements, Transcriptional; D014158:Transcription, Genetic; D019076:Transgenes; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D014764:Viral Proteins; C054366:herpes simplex virus type 1-protein ICP6; D008156:Luciferases