A gene therapy/targeted radiotherapy strategy for radiation cell kill by

Although [131I]meta-iodobenzylguanidine (MIBG) is currently one of the best agents available for targeted radiotherapy, its use is confined to a few neural crest derived tumours which accumulate the radiopharmaceutical via the noradrenaline transporter (NAT). To determine whether this drug could be used for the treatment of non-NAT expressing tumours following genetic manipulation, we previously showed that plasmid mediated transfection of NAT into a non-NAT expressing glioblastoma cell line, UVW, endowed the host cells with the capacity to actively accumulate [131I]MIBG. We now present data defining the conditions required for complete sterilisation of NAT transfected cells cultured as multicellular spheroids and treated with [131I]MIBG.

NAT transfected UVW cells, grown as monolayers and spheroids, were treated with various doses of [131I]MIBG and assessed for cell kill by clonogenic survival and measurement of spheroid volume over time (growth delay). Spheroids were left intact for different time periods to assess the effect of radiation crossfire on cell death.

Total clonogen sterilisation was observed when the cells were grown as three-dimensional spheroids and treated with 7 MBq/ml [131I]MIBG. The added benefit of radiation crossfire was demonstrated by the improvement in cell kill achieved by prolongation of the maintenance of [131I]MIBG treated spheroids in their three-dimensional form, before disaggregation and clonogenic assay. When left intact for 48 h after treatment, spheroid cure was achieved by exposure to 6 MBq/ml [131I]MIBG. These results demonstrate that the efficiency of cell kill by [131I]MIBG targeted therapy is strongly dependent on beta-particle crossfire irradiation. This gene therapy/targeted radiotherapy strategy has potential for [131I]MIBG mediated cell kill in tumours other than those derived from the neural crest.