title: Expression in UVW glioma cells of the noradrenaline transporter gene, driven by the telomerase RNA promoter, induces active uptake of [131I]MIBG and clonogenic cell kill.
abstract: One of the most effective ways to kill cancer cells is by treatment of tumours with radiation. However, the administered dose of radiation to the tumour is limited by normal tissue toxicity. Strategies which decrease normal tissue exposure relative to tumour dose are urgently sought. One such promising scheme involves gene transfer, leading to the introduction of transporters specific for pharmaceuticals which can be labelled with radionuclides. We have previously demonstrated in vitro, that transfer of the noradrenaline transporter (NAT) gene, under viral promoter control, induces in host cells the active accumulation of the radiopharmaceutical [131I]meta-iodobenzylguanidine ([131I]MIBG) which results in kill of clonogens. We now report 17-fold enhancement of [131I]MIBG uptake by UVW glioma cells transfected with the NAT gene whose expression is driven by the human telomerase RNA (hTR) promoter (70% the uptake achieved by the strong viral promoter). Multicellular spheroids composed of hTR-NAT-transfected UVW cells exhibited dose-dependent susceptibility to treatment with [131I]MIBG. This was demonstrated by decreased survival of clonogens and complete sterilization of clonogens derived from spheroids and also failure of spheroids to regrow after administration of 7 MBq/ml [131I]MIBG. These data suggest hTR regulated expression of NAT may be an effective gene therapy strategy.
authors.affiliation: Department of Radiation Oncology, University of Glasgow, CRC Beatson Laboratories, Garscube Estate, Bearsden, Glasgow, G61 1BD, UK. gpma55@udcf.gla.ac.uk
authors.forename: M
authors.initials: M
authors.lastname: Boyd
authors.forename: R J
authors.initials: RJ
authors.lastname: Mairs
authors.forename: S C
authors.initials: SC
authors.lastname: Mairs
authors.forename: L
authors.initials: L
authors.lastname: Wilson
authors.forename: A
authors.initials: A
authors.lastname: Livingstone
authors.forename: S H
authors.initials: SH
authors.lastname: Cunningham
authors.forename: M M
authors.initials: MM
authors.lastname: Brown
authors.forename: M
authors.initials: M
authors.lastname: Quigg
authors.forename: W N
authors.initials: WN
authors.lastname: Keith
mesh_terms: D019797:3-Iodobenzylguanidine / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002417:Cattle; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics*; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D027981:Symporters / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D050484:Norepinephrine Plasma Membrane Transport Proteins; D019275:Radiopharmaceuticals; C493227:SLC6A2 protein, human; D027981:Symporters; D019797:3-Iodobenzylguanidine