Application of targeted radiotherapy/gene therapy to bladder cancer cell lines.
OBJECTIVE
A targeted radiotherapy/gene therapy strategy for transitional cell carcinoma of bladder is described, using [131I]meta-iodobenzylguanidine ([131I]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 [131I]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 [131I]MIBG, was assessed by clonogenic assay.


RESULTS
NAT gene transfected cells exhibited a significantly increased active uptake of [131I]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 [131I]MIBG and dose-dependent cell kill. This strategy could produce a promising new treatment option for bladder cancer.
Fullerton
Natasha E
NE
Centre for Oncology and Applied Pharmacology, University of Glasgow, Cancer Research UK Beatson Laboratories, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK. n.fullerton@beatson.gla.ac.uk
Mairs
Robert J
RJ
Kirk
David
D
Keith
W Nicol
WN
Carruthers
Ross
R
McCluskey
Anthony G
AG
Brown
Mary
M
Wilson
Lesley
L
Boyd
Marie
M
D019797:3-Iodobenzylguanidine / Q000627:therapeutic use; D002295:Carcinoma, Transitional Cell / Q000628:therapy*; D045744:Cell Line, Tumor; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011878:Radiotherapy / Q000379:methods*; D027981:Symporters / Q000235:genetics; D019098:Telomerase / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000628:therapy*
D007457:Iodine Radioisotopes; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493227:SLC6A2 protein, human; D027981:Symporters; D019797:3-Iodobenzylguanidine; D019098:Telomerase