title: In vivo evaluation of a cancer therapy strategy combining HSV1716-mediated oncolysis with gene transfer and targeted radiotherapy.
abstract: Oncolytic herpes viruses show promise for cancer treatment. However, it is unlikely that they will fulfill their therapeutic potential when used as monotherapies. An alternative strategy is to use these viruses not only as oncolytic agents but also as a delivery mechanism of therapeutic transgenes to enhance tumor cell killing. The herpes simplex virus 1 deletion mutant HSV1716 is a conditionally replicating oncolytic virus that selectively replicates in and lyses dividing tumor cells. It has a proven safety profile in clinical trials and has demonstrated efficacy as a gene-delivery vehicle. To enhance its therapeutic potential, we have engineered HSV1716 to convey the noradrenaline transporter (NAT) gene (HSV1716/NAT), whose expression endows infected cells with the capacity to accumulate the noradrenaline analog metaiodobenzylguanidine (MIBG). Thus, the NAT gene-infected cells are susceptible to targeted radiotherapy using radiolabeled (131)I-MIBG, a strategy that has already shown promise for combined targeted radiotherapy-gene therapy in cancer cells after plasmid-mediated transfection.
  
  
  METHODS
  We used HSV1716/NAT as a dual cell lysis-gene delivery vehicle for targeting the NAT transgene to human tumor xenografts in vivo.
  
  
  RESULTS
  In tumor xenografts that did not express NAT, intratumoral or intravenous injection of HSV1716/NAT induced the capacity for active uptake of (131)I-MIBG. Administration of HSV1716/NAT and (131)I-MIBG resulted in decreased tumor growth and enhanced survival relative to injection of either agent alone. Efficacy was dependent on the scheduling of delivery of the 2 agents.
  
  
  CONCLUSIONS
  These findings support a role for combination radiotherapy-gene therapy for cancer using HSV1716 expressing the NAT transgene and targeted radionuclide therapy.
authors.affiliation: Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom.
authors.forename: Annette
authors.initials: A
authors.lastname: Sorensen
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mairs
authors.forename: Lynne
authors.initials: L
authors.lastname: Braidwood
authors.forename: Craig
authors.initials: C
authors.lastname: Joyce
authors.forename: Joe
authors.initials: J
authors.lastname: Conner
authors.forename: Sally
authors.initials: S
authors.lastname: Pimlott
authors.forename: Moira
authors.initials: M
authors.lastname: Brown
authors.forename: Marie
authors.initials: M
authors.lastname: Boyd
mesh_terms: D019797:3-Iodobenzylguanidine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003131:Combined Modality Therapy; D004274:DNA, Recombinant / Q000235:genetics; D018014:Gene Transfer Techniques; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000235:genetics; D050504:Oncolytic Viruses / Q000235:genetics*; D017384:Sequence Deletion; D013997:Time Factors
chemical_list: D004274:DNA, Recombinant; D050484:Norepinephrine Plasma Membrane Transport Proteins; D019797:3-Iodobenzylguanidine