Telomerase-Driven Expression of the Sodium Iodide Symporter (NIS) for in Vivo Radioiodide Treatment of Cancer: A New Broad-Spectrum NIS-Mediated Antitumor Approach

Context: Telomerase promoters (hTERT and hTR) are useful for transcriptional targeting in gene therapy models of cancer. Telomerase-driven expression of the sodium iodide symporter (NIS) in tumor cells has been successfully used as a reporter gene in vivo using positron emission tomography (PET) ima...

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Published in:The journal of clinical endocrinology and metabolism 2011-09, Vol.96 (9), p.E1435-E1443
Main Authors: Riesco-Eizaguirre, Garcilaso, De la Vieja, Antonio, Rodríguez, Irene, Miranda, Soledad, Martín-Duque, Pilar, Vassaux, Georges, Santisteban, Pilar
Format: Article
Language:English
Subjects:
Animal models
Animals
Cell Line, Tumor
Genetic Therapy - methods
Humans
Iodine Radioisotopes - therapeutic use
Mice
Neoplasm Transplantation
Neoplasms - genetics
Neoplasms - metabolism
Neoplasms - radiotherapy
Promoter Regions, Genetic
Symporters - genetics
Symporters - metabolism
Telomerase - genetics
Telomerase - metabolism
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Summary:Context: Telomerase promoters (hTERT and hTR) are useful for transcriptional targeting in gene therapy models of cancer. Telomerase-driven expression of the sodium iodide symporter (NIS) in tumor cells has been successfully used as a reporter gene in vivo using positron emission tomography (PET) imaging. Objective: The aim of this study was to investigate the NIS-mediated therapeutic effect of telomerase promoters in a wide variety of human cancer cell lines. Design and Methods: Promoter fragments from either hTERT or hTR were used to drive the expression of NIS in cell lines derived from melanoma (M14), breast (MDA-MB-231), colon (HT-29), lung (H460), ovarian (OVCAR-3), and thyroid (TPC-1) carcinomas. Iodide uptake assays, protein immunodetection, and clonigenic assays were used to confirm NIS functional expression and the 131I-mediated cytopathic effect. Tumor xenografts in mice were infected with hTERT and hTR and then treated using radioiodide. Results: Both promoters were selectively active in cancer cells that were effectively killed by exposure to 131I. One single dose of 1 mCi 131I markedly suppressed tumor growth of melanoma-derived tumor xenografts compared with controls. This effect was more modest in colon cancer-derived xenografts in part due to the reduced infectivity and the tumor cystic nature. The therapeutic effect of hTR promoter was found to be stronger than that of hTERT promoter. Conclusions: These results demonstrate that telomerase-driven expression of NIS could potentially have applications for 131I therapy of a wide variety of cancers. Additionally, this is the first study to report NIS-mediated 131I therapy of melanoma tumors in vivo.
ISSN:0021-972X
1945-7197
DOI:10.1210/jc.2010-2373