title: Wild-type p53 enhances the cytotoxic effect of radionuclide gene therapy using sodium iodide symporter in a murine anaplastic thyroid cancer model.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Nuclear Medicine, Seoul National University College of Medicine, 28 Yungun-dong, Chongno-gu, Seoul, 110-744, Korea.
authors.forename: Yong Jin
authors.initials: YJ
authors.lastname: Lee
authors.forename: June-Key
authors.initials: JK
authors.lastname: Chung
authors.forename: Joo Hyun
authors.initials: JH
authors.lastname: Kang
authors.forename: Jae Min
authors.initials: JM
authors.lastname: Jeong
authors.forename: Dong Soo
authors.initials: DS
authors.lastname: Lee
authors.forename: Myung Chul
authors.initials: MC
authors.lastname: Lee
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011868:Radioisotopes / Q000627:therapeutic use*; D019275:Radiopharmaceuticals / Q000627:therapeutic use; D027981:Symporters / Q000235:genetics / Q000627:therapeutic use*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000628:therapy*; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000627:therapeutic use*; D000099209:Sodium-Iodide Symporters
chemical_list: D011868:Radioisotopes; D019275:Radiopharmaceuticals; D027981:Symporters; D016159:Tumor Suppressor Protein p53; D000099209:Sodium-Iodide Symporters