A gene therapy/targeted radiotherapy strategy for radiation cell kill by [I-131]meta-iodobenzylguanidine

Background Although [I-131]meta-iodobenzylguanidine (MIBG) is currently one of the best agents available for targeted radiotherapy, its use is confine d to a few neural crest derived tumours which accumulate the radiopharmaceu tical via the noradrenaline transporter (NAT). To determine whether this dr ug could be used for the treatment of non-NAT expressing tumours following genetic manipulation, we previously showed that plasmid mediated transfecti on of NAT into a non-NAT expressing glioblastoma cell line, UVW, endowed th e host cells with the capacity to actively accumulate [I-131]MIBG. We now p resent data defining the conditions required for complete sterilisation of NAT transfected cells cultured as multicellular spheroids and treated with [I-131]MIBG. Methods NAT transfected UVW cells, grown as monolayers and spheroids, were treated with various doses of [I-131]MIBG and assessed for cell kill by clo nogenic survival and measurement of spheroid volume over time (growth delay ). Spheroids were left intact for different time periods to assess the effe ct of radiation crossfire on cell death. Results and Conclusions Total clonogen sterilisation was observed when the cells were grown as three-dimensional spheroids and treated with 7 MBq/ml [ I-131]MIBG. The, added benefit of radiation crossfire was demonstrated by t he improvement in cell kill achieved by prolongation of the maintenance of [I-131]MIBG treated spheroids in their three-dimensional form, before disag gregation and clonogenic assay. When left intact for 48 h after treatment, spheroid cure was achieved by exposure to 6 MBq/ml [I-131]MIBG. These resul ts demonstrate that the efficiency of cell kill by [I-131]MIBG targeted the rapy is strongly dependent on beta -particle crossfire irradiation. This ge ne therapy/targeted radiotherapy strategy has potential for [I-131]MIBG med iated cell kill in tumours other than those derived from the neural crest. Copyright (C) 2000 John Wiley & Sons, Ltd.