title: Comparison of radiohaloanalogues of meta-iodobenzylguanidine (MIBG) for a combined gene- and targeted radiotherapy approach to bladder carcinoma.
abstract: Targeted radiotherapy using radiolabelled meta-iodobenzylguanidine (MIBG) is a promising treatment option for bladder cancer, restricting the effects of radiotherapy to malignant cells thereby increasing efficacy and decreasing morbidity of radiotherapy. We investigated the efficacy of a combined gene therapy and targeted radiotherapy approach for bladder cancer using radiolabelled MIBG. The effectiveness of alternative radiohalogens and alternative preparations of radiolabelled MIBG for this therapeutic strategy were compared. Bladder cancer cells, EJ138, were transfected with a gene encoding the noradrenaline transporter (NAT) under the control of a tumour specific telomerase promoter, enabling them to actively take up radiolabelled MIBG. This resulted in tumour-specific cell kill. Uptake and retention of radioactivity in cells transfected with the NAT gene were compared with that obtained in cells transfected with the sodium iodide symporter (NIS) gene. Substantially greater uptake and longer retention of radioactivity in NAT-transfected cells was observed. Carrier-added (c.a.) [131I]MIBG, no-carrier added (n.c.a.) [131I]MIBG, and [211At]-labelled benzylguanidine (i.e. [211At] meta-astatobenzylguanidine (MABG)) were compared with respect to efficiency of induction of cell kill. N.c.a[(131)I]MIBG was more cytotoxic than c.a.[131I]MIBG. However, the alpha-emitter [211At]MABG was, by three orders of magnitude, more effective in causing tumour cell kill than the beta-emitter [131I]MIBG. We conclude that NAT gene transfer combined with the administration of n.c.a.[131I]MIBG or [211At]MABG, is a promising novel treatment approach for bladder cancer therapy.
authors.affiliation: Centre for Oncology & Applied Pharmacology, University of Glasgow, Cancer Research, UK.
authors.forename: Natasha E
authors.initials: NE
authors.lastname: Fullerton
authors.forename: Marie
authors.initials: M
authors.lastname: Boyd
authors.forename: Susan C
authors.initials: SC
authors.lastname: Ross
authors.forename: Sally L
authors.initials: SL
authors.lastname: Pimlott
authors.forename: John
authors.initials: J
authors.lastname: Babich
authors.forename: David
authors.initials: D
authors.lastname: Kirk
authors.forename: Michael R
authors.initials: MR
authors.lastname: Zalutsky
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mairs
mesh_terms: D019797:3-Iodobenzylguanidine / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000512:Alpha Particles / Q000627:therapeutic use; D001246:Astatine / Q000737:chemistry / Q000627:therapeutic use*; D001610:Beta Particles / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy / Q000379:methods; D004307:Dose-Response Relationship, Radiation; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007452:Iodates / Q000737:chemistry / Q000627:therapeutic use; D007457:Iodine Radioisotopes / Q000737:chemistry / Q000627:therapeutic use*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013329:Structure-Activity Relationship; D027981:Symporters / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000532:radiotherapy / Q000628:therapy*; D000099209:Sodium-Iodide Symporters
chemical_list: D019797:3-Iodobenzylguanidine; D001246:Astatine; D007452:Iodates; D007457:Iodine Radioisotopes; D050484:Norepinephrine Plasma Membrane Transport Proteins; D019275:Radiopharmaceuticals; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C032285:sodium iodate