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

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.