Application of targeted radiotherapy/gene therapy to bladder cancer cell lines

Objectives: A targeted radiotherapy/gene therapy strategy for transitional cell carcinoma of bladder is described, using [I-131] meta-iodobenzylguanidine ([I-131]MIBG), a radionuclide combined with a tumour-seeking drug. The aim is to decrease side effects from radiation toxicity, while increasing radiation dose to tumour. This tumour cell kill approach is augmented by radiological bystander effects. Methods: The bladder cancer cell line EJ138 was transfected with a gene encoding the noradrenaline transporter (NAT) under the control of tumour-specific telomerase promoters. Resulting uptake of [I-131]MIBG was assessed by gamma-counting of cell lysates, and NAT transgene expression by real-time RT-PCR. Cell kill of monolayers and disaggregated spheroids, dosed with [I-131]MIBG, was assessed by clonogenic assay. Results: NAT gene transfected cells exhibited a significantly increased active uptake of [I-131]MIBG, leading to dose-dependent cell kill. Clonogenic assay of disaggregated spheroids, a three-dimensional model, suggested cell kill via bystander effects. Conclusions: Expression of a functional NAT after in vitro transfection of bladder cancer cells with the NAT gene under the control of telomerase promoters leads to active uptake of [I-131]MIBG and dose-dependent cell kill. This strategy could produce a promising new treatment option for bladder cancer. (C) 2004 Elsevier B.V. All rights reserved.