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

McCluskey, A.G., Mairs, R.J. , Sorensen, A., Robson, T., McCarthy, H.O., Pimlott, S.L. , Babich, J.W., Champion, S. and Boyd, M. (2013) Gamma irradiation and targeted radionuclides enhance the expression of the noradrenaline transporter transgene controlled by the radio-inducible p21^WAF1/CIP1 promoter. Radiation Research, 179(3), pp. 282-292. (doi: 10.1667/RR3030.1)

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, p21WAF1/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 [131I]MIBG, which led to increased sensitivity to the radiopharmaceutical. Pretreatment of transfected cells with γ radiation or the radiopharmaceuticals [123I]MIBG or [131I]MIBG induced dose- and time-dependent increases in subsequent [131I]MIBG uptake and led to enhanced efficacy of [131I]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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Pimlott, Dr Sally and McCluskey, Mr Anthony and Mairs, Professor Robert and Champion, Dr Sue and Sorensen, Dr Annette and Boyd, Dr Marie
• Authors: McCluskey, A.G., Mairs, R.J., Sorensen, A., Robson, T., McCarthy, H.O., Pimlott, S.L., Babich, J.W., Champion, S., and Boyd, M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Radiation Research
• ISSN: 0033-7587
• ISSN (Online): 1938-5404