title: Preclinical assessment of strategies for enhancement of metaiodobenzylguanidine therapy of neuroendocrine tumors.
abstract: By virtue of its high affinity for the norepinephrine transporter (NET), [(131)I]metaiodobenzylguanidine ([(131)I]MIBG) has been used for the therapy of tumors of neuroectodermal origin for more than 25 years. Although not yet universally adopted, [(131)I]MIBG targeted radiotherapy remains a highly promising means of management of neuroblastoma, pheochromocytoma, and carcinoids. Appreciation of the mode of conveyance of [(131)I]MIBG into malignant cells and of factors that influence the activity of the uptake mechanism has indicated a variety of means of increasing the effectiveness of this type of treatment. Studies in model systems revealed that radiolabeling of MIBG to high specific activity reduced the amount of cold competitor, thereby increasing tumor dose and minimizing pressor effects. Increased radiotoxicity to targeted tumors might also be achieved by the use of the α-particle emitter [(211)At]astatine rather than (131)I as radiolabel. Recently it has been demonstrated that potent cytotoxic bystander effects were induced by [(131)I]MIBG, [(123)I]MIBG, and [(211)At]meta-astatobenzylguanidine. Discovery of the structure of bystander factors could increase the therapeutic ratio achievable by MIBG targeted radiotherapy. [(131)I]MIBG combined with topotecan produced supra-additive cytotoxicity in vitro and tumor growth delay in vivo. The enhanced antitumor effect was consistent with a failure to repair DNA damage. Initial findings suggest that further enhancement of efficacy might be achieved by triple combination therapy with drugs that disrupt alternative tumor-specific pathways and synergize not only with [(131)I]MIBG abut also with topotecan. With these ploys, it is expected that advances will be made toward the optimization of [(131)I]MIBG therapy of neuroectodermal tumors.
authors.affiliation: Radiation Oncology, Division of Cancer Science and Molecular Pathology, University of Glasgow, Cancer Research UK, Beatson Laboratories, Glasgow, Scotland. Robert.Mairs@glasgow.ac.uk
authors.forename: Rob J
authors.initials: RJ
authors.lastname: Mairs
authors.forename: Marie
authors.initials: M
authors.lastname: Boyd
mesh_terms: D019797:3-Iodobenzylguanidine / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D024201:Bystander Effect / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D018358:Neuroendocrine Tumors / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*
chemical_list: D004791:Enzyme Inhibitors; D019797:3-Iodobenzylguanidine