An efficient targeted radiotherapy/gene therapy strategy utilising human telomerase promoters and radioastatine and harnessing radiation-mediated bystander effects

Boyd, M. et al. (2004) An efficient targeted radiotherapy/gene therapy strategy utilising human telomerase promoters and radioastatine and harnessing radiation-mediated bystander effects. Journal of Gene Medicine, 6(8), pp. 937-947. (doi:10.1002/jgm.578)

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Publisher's URL: http://dx.doi.org/10.1002/jgm.578

Abstract

Background<br/>Targeted radiotherapy achieves malignant cell-specific concentration of radiation dosage by tumour-affinic molecules conjugated to radioactive atoms. Combining gene therapy with targeted radiotherapy is attractive because the associated cross-fire irradiation of the latter induces biological bystander effects upon neighbouring cells overcoming low gene transfer efficiency.<br/> Methods<br/>We sought to maximise the tumour specificity and efficacy of noradrenaline transporter (NAT) gene transfer combined with treatment using the radiopharmaceutical meta-[<sup>131</sup>1] iodobenzylguanidine ([<sup>131</sup>1]MIBG). Cell-kill was achieved by treatment with the beta-decay particle emitter [<sup>131</sup>1]MIBG or the alpha-particle emitter [<sup>211</sup>At]MABG. We utilised our novel transfected mosaic spheroid model (TMS) to determine whether this treatment strategy could result in sterilisation of spheroids containing only a small proportion of NAT-expressing cells.<br/> Results<br/>The concentrations of [<sup>131</sup>1]MIBG and [<sup>211</sup>At]MABG required to reduce to 0.1% the survival of clonogens derived from the TMS composed of 100% of NAT gene-transfected cells were 1.5 and 0.004 MBq/ml (RSV promoter), 8.5 and 0.0075 MBq/ml (hTR promoter), and 9.0 and 0.008 MBq/ml (hTERT promoter), respectively. The concentrations of radiopharmaceutical required to reduce to 0.1% the survival of clonogens derived from 5% RSV/NAT and 5% hTERT/NAT TMS were 14 and 23 MBq/ml, respectively, for treatment with [<sup>131</sup>1]MIBG and 0.018 and 0.028 MBq/ml, respectively, for treatment with [<sup>211</sup>At]MABG.<br/> Conclusions<br/>These results indicate that the telomerase promoters have the capacity to drive the expression of the NAT. The potency of [<sup>211</sup>At]MABG is approximately three orders of magnitude greater than that of [<sup>131</sup>1]MIBG. Spheroids composed of only 5% of cells expressing NAT under the control of the RSV or hTERT promoter were sterilised by radiopharmaceutical treatment. This observation is indicative of bystander cell-kill.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Keith, Professor Nicol and Mairs, Professor Robert and Boyd, Dr Marie
Authors: Boyd, M., Mairs, R.J., Keith, W.N., Ross, S.C., Welsh, P., Akabani, G., Owens, J., Vaidyanathan, G., Carruthers, R., Dorrens, J., and Zalutsky, M.R.
Subjects:R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Q Science > QH Natural history > QH426 Genetics
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Journal of Gene Medicine
ISSN:1099-498X

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