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Glial fibrillary acidic protein promoters direct adenovirus early 1A gene and human telomerase reverse transcriptase promoters direct sodium iodide symporter expression for malignant glioma radioiodine therapy

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Abstract

Malignant glioma can be treated with radioiodine following transfection with human sodium iodide symporter (hNIS) gene. Ad-Tp-E1A-Gp-NIS is engineered with human telomerase reverse transcriptase (hTERT) and glial fibrillary acidic protein (GFAP) promoters to express early region 1A (E1A) and hNIS genes, which may be useful in targeted gene therapy. The Ad-Tp-E1A-Gp-NIS was constructed and purified using the E1A and hNIS genes regulated by the hTERT and GFAP promoters, respectively. Glioma cells were infected by Ad-Tp-E1A-Gp-NIS. Selective replication ability of Ad-Tp-E1A-Gp-NIS was then evaluated by plaque forming assay, transgene expression by Western blot, 125I-iodide uptake and efflux, clonogenicity following 131I-iodide treatment in the tumor cells, and radioiodine therapy using nude mouse model. The Ad-Tp-E1A-Gp-NIS could selectively replicate; the hNIS gene was successfully expressed under the GFAP promoter. Western blot analyses using E1A- and hNIS-specific antibodies revealed two bands of approximately 40 and 70 kDa. In addition, the cells showed about 93.4 and 107.1 times higher 125I uptake in U251 and U87 cells than in the control cells, respectively. Clonogenic assay indicated that >90 % of cells transfected with Ad-Tp-E1A-Gp-NIS were killed. The Ad-Tp-E1A-Gp-NIS-transfected and 2 mCi 131I-injected U87 xenograft nude mice survived the longest among the three groups. Ad-Tp-E1A-Gp-NIS has a good ability of selective replication and strong antitumor selectivity. An effective therapy of 131I was achieved activity in malignant glioma cells after induction of tumor-specific iodide uptake activity by GFAP promoter-directed hNIS gene expression in vitro and in vivo.

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Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (to Jian TAN) (No. 81171372) (to Wei LI) (No. 81301244) and the Tianjin Research Program of Application Foundation and Advanced Technology (to Jian TAN) (No. 12JCZDJC26000) and National Key Clinical Specialty Project of China.

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Authors and Affiliations

  1. Department of Nuclear Medicine, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052, People’s Republic of China

    Wei Li, Jian Tan, Peng Wang, Ning Li & Chengxia Li

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  1. Wei Li
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  2. Jian Tan
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  3. Peng Wang
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  4. Ning Li
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Correspondence to Jian Tan.

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Li, W., Tan, J., Wang, P. et al. Glial fibrillary acidic protein promoters direct adenovirus early 1A gene and human telomerase reverse transcriptase promoters direct sodium iodide symporter expression for malignant glioma radioiodine therapy. Mol Cell Biochem 399, 279–289 (2015). https://doi.org/10.1007/s11010-014-2254-5

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  • DOI: https://doi.org/10.1007/s11010-014-2254-5

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