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

To evaluate the role of p53 in radionuclide gene therapy, we investigated the cytotoxic effect of I-131 and Re-188 following cotransfection of the sodium iodide symporter (NIS) and wild-type p53 (wt-p53) genes into cancer cells. The NIS gene was transfected to human anaplastic thyroid carcinoma cells (ARO) expressing mutant p53 (mt-p53) using liposomes. The uptakes of I-125 and Re-188 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 I-131 and Re-188, 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, Re-188 or saline was injected intraperitoneally into the mice, and the tumours were measured using a calliper for 4 weeks. In ARO-N cells, the uptakes of I-125 and Re-188 were 505.16 +/- 21.30 pmol/10(6) cells and 13,875.20 +/- 504.85 cpm/10(6) cells at 30 min, respectively. There was no difference between the survival rates of ARO cells and ARO-N cells after incubation with I-131 or Re-188. When Ad-p53 was transduced to ARO-N cells, the survival rate of wt-p53-expressing ARO-N cells incubated with I-131 (18.5 MBq/5 ml) and Re-188 (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 Re-188 regressed to 20% of the initial volume. Growth of ARO-N tumour treated with I-131 or Re-188 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.