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

Abstract

To evaluate the role of p53 in radionuclide gene therapy, we investigated the cytotoxic effect of (131)I and (188)Re 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 (125)I and (188)Re 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 (131)I and (188)Re, 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, (188)Re 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 (125)I and (188)Re 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 (131)I or (188)Re. When Ad-p53 was transduced to ARO-N cells, the survival rate of wt-p53-expressing ARO-N cells incubated with (131)I (18.5 MBq/5 ml) and (188)Re (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 (188)Re regressed to 20% of the initial volume. Growth of ARO-N tumour treated with (131)I or (188)Re 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.