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Gamma irradiation and targeted radionuclides enhance the expression of the noradrenaline transporter transgene controlled by the radio-inducible p21(WAF1/CIP1) promoter

Author(s): A. G. McCluskey, R. J. Mairs, A. Sorensen, T. Robson, H. O. McCarthy, S. L. Pimlott, J. W. Babich, S. Champion, M. Boyd

Abstract:
The use of radiation-inducible promoters to drive transgene expression offers the possibility of temporal and spatial regulation of gene activation. This study assessed the potential of one such promoter element, p21(WAF1/CIP1) (WAF1), to drive expression of the noradrenaline transporter (NAT) gene, which conveys sensitivity to radioiodinated meta-iodobenzylguanidine (MIBG). An expression vector containing NAT under the control of the radiation-inducible WAF1 promoter (pWAF/NAT) was produced. The non-NAT expressing cell lines UVW (glioma) and HCT116 (colorectal cancer) were transfected with this construct to assess radiation-controlled WAF1 activation of the NAT gene. Transfection of UVW and HCT cells with pWAF/NAT conferred upon them the ability to accumulate [(131)I]MIBG, which led to increased sensitivity to the radiopharmaceutical. Pretreatment of transfected cells with gamma radiation or the radiopharmaceuticals [(123)I]MIBG or [(131)I]MIBG induced dose- and time-dependent increases in subsequent [(131)I]MIBG uptake and led to enhanced efficacy of [(131)I]MIBG-mediated cell kill. Gene therapy using WAF1-driven expression of NAT has the potential to expand the use of this therapeutic modality to tumors that lack a radio-targetable feature.

Full version: Available here

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ISBN: 1938-5404 (Electronic)0033-7587 (Linking)
Publication Year: 2013
Periodical: Radiat Res
Periodical Number: 3
Volume: 179
Pages: 282-92
Author Address: Experimental Targeted Radiation Therapeutics Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom. anthony.mccluskey@strath.ac.uk