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Wild-type p53 enhances the cytotoxic effect of radionuclide gene therapy using sodium iodide symporter in a murine anaplastic thyroid cancer model

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

To evaluate the role of p53 in radionuclide gene therapy, we investigated the cytotoxic effect of 131I and 188Re following cotransfection of the sodium iodide symporter (NIS) and wild-type p53 (wt-p53) genes into cancer cells.

Methods

The NIS gene was transfected to human anaplastic thyroid carcinoma cells (ARO) expressing mutant p53 (mt-p53) using liposomes. The uptakes of 125I and 188Re were measured in the transfected (ARO-N) and wild-type cell lines (ARO). A recombinant adenovirus-5 vector containing a CMV promoter and wt-p53 cDNA, called Ad-p53, was established and transduced to ARO and ARO-N cells. After incubating cells with 131I and 188Re, the survival rate of each cell line was measured using a clonogenic assay. For radionuclide gene therapy in an animal model, Ad-p53 was injected directly into ARO and ARO-N tumours which were transplanted to nude mice. Two days later, 188Re or saline was injected intraperitoneally into the mice, and the tumours were measured using a calliper for 4 weeks.

Results

In ARO-N cells, the uptakes of 125I and 188Re were 505.16±21.30 pmol/106 cells and 13,875.20±504.85 cpm/106 cells at 30 min, respectively. There was no difference between the survival rates of ARO cells and ARO-N cells after incubation with 131I or 188Re. When Ad-p53 was transduced to ARO-N cells, the survival rate of wt-p53-expressing ARO-N cells incubated with 131I (18.5 MBq/5 ml) and 188Re (18.5 MBq/5 ml) decreased to 48.8±18.4% and 32.6±23.5%, respectively. In the nude mice experiment, ARO and ARO-N tumours gradually grew up to six to eight times larger than the initial volume. ARO and ARO-N tumours transduced with Ad-p53 continued to grow. However, the ARO-N tumours treated with Ad-p53 and 185 MBq of 188Re regressed to 20% of the initial volume.

Conclusion

Growth of ARO-N tumour treated with 131I or 188Re was significantly inhibited by Ad-p53 transduction in vivo as well as in vitro. Transfection of the NIS gene into human anaplastic thyroid cancer induced the accumulation of beta-emitter radionuclides, and cotransfection with a wt-p53 gene enhanced the cytotoxic effect.

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Acknowledgments

This work was supported by a Korea Research Foundation Grant funded by the Korean Government (MOEHRD) (KRF-2003-E-00168)

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Authors and Affiliations

  1. Department of Nuclear Medicine, Seoul National University College of Medicine, 28 Yungun-dong, Chongno-gu, Seoul, 110-744, Korea

    Yong Jin Lee, June-Key Chung, Jae Min Jeong, Dong Soo Lee & Myung Chul Lee

  2. Cancer Research Institute, Seoul National University College of Medicine, 28 Yungun-dong, Chongno-gu, Seoul, 110-744, Korea

    Yong Jin Lee, June-Key Chung & Jae Min Jeong

  3. Tumor Immunity Medical Research Center, Seoul National University College of Medicine, 28 Yungun-dong, Chongno-gu, Seoul, 110-744, Korea

    Yong Jin Lee & June-Key Chung

  4. Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, 75 Nowon-gil, Gongneung-Dong, Nowon-Gu, Seoul, 139-706, Korea

    Yong Jin Lee & Joo Hyun Kang

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  1. Yong Jin Lee
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  2. June-Key Chung
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  3. Joo Hyun Kang
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Correspondence to June-Key Chung.

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Lee, Y.J., Chung, JK., Kang, J.H. et al. Wild-type p53 enhances the cytotoxic effect of radionuclide gene therapy using sodium iodide symporter in a murine anaplastic thyroid cancer model. Eur J Nucl Med Mol Imaging 37, 235–241 (2010). https://doi.org/10.1007/s00259-009-1251-5

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  • DOI: https://doi.org/10.1007/s00259-009-1251-5

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