title: Assessment in vitro of a novel therapeutic strategy for glioma, combining herpes simplex virus HSV1716-mediated oncolysis with gene transfer and targeted radiotherapy.
abstract: Genetically engineered herpes simplex virus ICP34.5 null mutants replicate only in dividing cells and have shown potential for the treatment of malignant disease, including glioma. Phase I trials have demonstrated the safety of these viruses in various clinical settings but it is envisaged that for full efficacy they will be used in combination with other therapeutic modalities. To enhance virus-induced tumour cytotoxicity, we have engineered an ICP34.5 null mutant (HSV1716) of HSV1 which expresses the noradrenaline transporter gene (NAT). This virus is designated HSV1716/NAT. We have shown previously that introduction of the NAT gene into a range of tumour cells, via plasmid-mediated transfection, conferred the capacity for active uptake of the radiopharmaceutical [131I]MIBG and resulted in dose-dependent toxicity. In this study, combination therapy utilising HSV1716/NAT and [131I]MIBG was assessed in vitro by the MTT assay. We demonstrate that the NAT gene, introduced by HSV1716/NAT into cultured glioma cells, was expressed 1 h after viral infection, enabling active uptake of [131I]MIBG. The combination of viral oncolysis and induced radiopharmaceutical uptake resulted in significantly enhanced cytotoxicity compared to either agent alone and the response was dose- and time-dependent. These studies show that the combination of oncolytic HSV therapy with targeted radiotherapy has the potential for effective tumour cell kill and warrants further investigation as a treatment for malignant glioma.
authors.affiliation: Targeted Therapies Group, Centre for Oncology and Applied Pharmacology, University of Glasgow, Cancer Research UK Beatson Laboratories, and Crusade Laboratories Ltd., Southern General Hospital, Glasgow G61 1BD, Scotland, UK.
authors.forename: M
authors.initials: M
authors.lastname: Quigg
authors.forename: R J
authors.initials: RJ
authors.lastname: Mairs
authors.forename: S M
authors.initials: SM
authors.lastname: Brown
authors.forename: J
authors.initials: J
authors.lastname: Harland
authors.forename: P
authors.initials: P
authors.lastname: Dunn
authors.forename: R
authors.initials: R
authors.lastname: Rampling
authors.forename: A
authors.initials: A
authors.lastname: Livingstone
authors.forename: L
authors.initials: L
authors.lastname: Wilson
authors.forename: M
authors.initials: M
authors.lastname: Boyd
mesh_terms: D019797:3-Iodobenzylguanidine / Q000493:pharmacokinetics*; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D018014:Gene Transfer Techniques; D005818:Genetic Engineering; D005910:Glioma / Q000235:genetics / Q000628:therapy* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D051379:Mice; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000235:genetics / Q000502:physiology; D050130:Oncolytic Virotherapy / Q000379:methods*; D011878:Radiotherapy / Q000379:methods; D013329:Structure-Activity Relationship; D013997:Time Factors; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D050484:Norepinephrine Plasma Membrane Transport Proteins; D019797:3-Iodobenzylguanidine