Noradrenaline transporter gene transfer for radiation cell kill by 131I meta-iodobenzylguanidine

Meta-iodobenzylguanidine conjugated to I-131-iodine is an effective agent for the targeted radiotherapy of tumors of neural crest origin which express the noradrenaline transporter (NAT). The therapeutic application of I-131 MIBG is : presently limited to the treatment of phaeochromocytoma, neuroblastoma, carcinoid and medullary thyroid carcinoma. To determine the feasibility of MIBG targeting for a wider range of tumor types, we employed plasmid-mediated transfer of the NAT gene into a human glioblastoma cell line (UVW) which does not express the NAT gene. This resulted in a 15-fold increase in uptake of MIBG by the host cells. A dose-dependent toxicity of I-131 MIBG to the transfectants was demonstrated using three methods: (1) survival of clonogens derived from monolayer culture; (2) survival of clonogens derived from disaggregated multicellular spheroids; and (3) spheroid growth delay. I-131 MIBG was twice as toxic to cells in spheroids compared with those in monolayers, consistent with a greater effect of radiation cross-fire (radiological bystander effect) from I-131 beta-radiation in the three-dimensional tumor spheroids. The highest concentration of I-131 MIBG tested (1 MBq/ml) was nontoxic to UVW control cells or spheroids transfected with the NAT gene in reverse orientation. These findings are encouraging for the development of NAT gene transfer-mediated I-131 MIBG therapy.