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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.
AuthorsNatasha E Fullerton, Marie Boyd, Susan C Ross, Sally L Pimlott, John Babich, David Kirk, Michael R Zalutsky, Robert J Mairs
JournalMedicinal chemistry (Shariqah (United Arab Emirates)) (Med Chem) Vol. 1 Issue 6 Pg. 611-8 (Nov 2005) ISSN: 1573-4064 [Print] Netherlands
PMID16787344 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Iodates
  • Iodine Radioisotopes
  • Norepinephrine Plasma Membrane Transport Proteins
  • Radiopharmaceuticals
  • Symporters
  • 3-Iodobenzylguanidine
  • sodium-iodide symporter
  • sodium iodate
  • Astatine
Topics
  • 3-Iodobenzylguanidine (chemical synthesis, pharmacokinetics, therapeutic use)
  • Alpha Particles (therapeutic use)
  • Astatine (chemistry, therapeutic use)
  • Beta Particles (therapeutic use)
  • Cell Line, Tumor
  • Cell Survival (drug effects)
  • Combined Modality Therapy (methods)
  • Dose-Response Relationship, Radiation
  • Genetic Therapy (methods)
  • Humans
  • Iodates (chemistry, therapeutic use)
  • Iodine Radioisotopes (chemistry, therapeutic use)
  • Norepinephrine Plasma Membrane Transport Proteins (biosynthesis, genetics)
  • Radiopharmaceuticals (chemical synthesis, pharmacokinetics, therapeutic use)
  • Structure-Activity Relationship
  • Symporters (biosynthesis, genetics)
  • Tumor Cells, Cultured
  • Urinary Bladder Neoplasms (radiotherapy, therapy)

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