A transfectant mosaic xenograft model for evaluation of targeted radiotherapy in combination with gene therapy in vivo

Mairs, R. , Ross, S., McCluskey, A. and Boyd, M. (2007) A transfectant mosaic xenograft model for evaluation of targeted radiotherapy in combination with gene therapy in vivo. Journal of Nuclear Medicine, 48(9), pp. 1519-1526. (doi: 10.2967/jnumed.107.042226)

Abstract

For gene therapy to be efficacious in the treatment of cancer, therapeutic transgenes must be limited in their expression to tumor cells and must be expressed at sufficiently high transcriptional levels. Moreover, the inadequacy of gene delivery must be overcome by induction of toxicity to neighboring nontargeted cells. Combining targeted radionuclide therapy with gene therapy using human telomerase promoters has shown promise in these respects, and the efficacy of this scheme has been assessed in vitro using transfectant mosaic tumor spheroids. To enable the evaluation of targeted radiotherapy combined with gene transfer in vivo, we have developed a transfectant mosaic xenograft (TMX model. Methods: Human telomerase promoters were used to drive expression of the noradrenaline transporter (NAT) transgene in 2 human cell lines (UVW and EJ138). Promoter activity was assessed in xenografts in nude mice by determination of the uptake of the radio p harm aceutical I-131-metaiodobenzylguanidine (I-131-MIBG) and by measurement of tumor growth. The efficacy of I-131-MIBG treatment was also assessed in TMXs to determine the delay in growth of tumors composed of various proportions of NAT-expressing cells-a likely clinical scenario after gene delivery in vivo. Results: In terms of induction of the capacity for active uptake of I-131-MIBG and the resultant inhibition of tumor growth in vivo, both telomerase promoters (hTR and hTERT) were similar in potency to the CMV (cytomegalovirus) promoter as controlling elements for the expression of the NAT transgene. In TMXs derived from UVW and EJ138 cells, I-131-MIBG uptake was proportional to NAT gene expression (r(s) = 0.910, P < 0.001 for UVW; r(s) = 0.971, P < 0.001 for EJ138). Inhibition of the growth of these tumors correlated with the fraction of NAT-transfected cells (r(s) = 0.910, P < 0.001 for UVW; r(s) = 0.971, P < 0.001 for EJ138), and substantial tumor growth delay was observed when 5% of the xenograft was composed of NAT-positive cells. Conclusion: TMXs constitute a suitable model to measure the efficacy of cancer gene therapy strategies when <100% of the tumor mass can be targeted to express the therapeutic transgene.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Mairs, Professor Robert and Boyd, Dr Marie
• Authors: Mairs, R., Ross, S., McCluskey, A., and Boyd, M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Nuclear Medicine
• ISSN: 0161-5505