Boyd M, Mairs R J, Cunningham S H, Mairs S C, McCluskey A, Livingstone A, Stevenson K, Brown M M, Wilson L, Carlin S, Wheldon T E
Department of Radiation Oncology, Glasgow University, UK.
J Gene Med. 2001 Mar-Apr;3(2):165-72. doi: 10.1002/1521-2254(2000)9999:9999<::AID-JGM158>3.0.CO;2-C.
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.
虽然[131I]间碘苄胍（MIBG）是目前可用于靶向放疗的最佳药物之一，但其应用局限于少数通过去甲肾上腺素转运体（NAT）摄取放射性药物的神经嵴来源肿瘤。为了确定这种药物在基因操作后是否可用于治疗不表达NAT的肿瘤，我们之前表明，通过质粒介导将NAT转染到不表达NAT的胶质母细胞瘤细胞系UVW中，可使宿主细胞具备主动摄取[131I]MIBG的能力。我们现在展示的数据定义了对培养为多细胞球体并经[131I]MIBG处理的NAT转染细胞进行完全灭菌所需的条件。
将培养为单层和球体的NAT转染UVW细胞用不同剂量的[131I]MIBG处理，并通过克隆存活和随时间测量球体体积（生长延迟）来评估细胞杀伤情况。将球体完整放置不同时间段，以评估辐射交叉火力对细胞死亡的影响。
当细胞培养为三维球体并用7 MBq/ml [131I]MIBG处理时，观察到克隆原完全灭菌。通过在[131I]MIBG处理的球体解体和克隆分析之前延长其三维形式的维持时间所实现的细胞杀伤改善，证明了辐射交叉火力的额外益处。处理后完整放置48小时，通过暴露于6 MBq/ml [131I]MIBG可实现球体治愈。这些结果表明，[131I]MIBG靶向治疗的细胞杀伤效率强烈依赖于β粒子交叉火力照射。这种基因治疗/靶向放疗策略在除神经嵴来源肿瘤之外的其他肿瘤中具有[131I]MIBG介导的细胞杀伤潜力。
