title: Tumor-targeted radionuclide imaging and therapy based on human sodium iodide symporter gene driven by a modified telomerase reverse transcriptase promoter.
abstract: Human telomerase reverse transcriptase (hTERT) is highly active in most cancer cells and, thus, could be used for tumor targeting. The human sodium iodide symporter (hNIS) gene is being actively researched as a potential radioactive iodine (radioiodine) gene therapy. In this study, we investigated the possibilities of using the hNIS gene driven by the hTERT promoter for molecular imaging and radioiodine gene therapy. Stable cell lines of hTERT-positive cells (Hep3B hepatoma) expressing hNIS, under the control of the 5mmTERT promoter, were generated using a retroviral system. Radioiodine uptake and efflux tests were performed, and a clonogenic assay was used to evaluate the in vitro cytotoxicity of 131I. Finally, scintigraphic, biodistribution, and radioiodine therapy studies were performed in vivo. Radioiodine uptake by 5mmTERT-NIS-transfected Hep3B cells was 22 times higher than by nontransfected Hep3B cells, and 5 times that of 5mmTERT-NIS-transfected U2-OS cells (p < 0.05). Clonogenic assays demonstrated that the survival rate of Hep3B-5mmTERT-NIS cells after 131I incubation was significantly lower than that of Hep3B cells (p < 0.001), and radioiodine accumulations in Hep3B-5mmTERT-NIS tumors were significantly higher than in wild-type tumors. In addition, technetium- 99m scintigraphy clearly visualized Hep3B-5mmTERT-NIS tumors. Moreover, after being treated with 111 MBq of 131I-labeled Hep3B-5mmTERT-NIS, tumor growth was retarded, whereas Hep3B tumor growth progressed. hTERT-positive tumors were successfully targeted by the NIS gene under the control of the 5mmTERT promoter. The described system could be useful for targeted molecular imaging and as a radioiodine gene therapy for cancer.
authors.affiliation: Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 110-744, South Korea.
authors.forename: Seung Hoo
authors.initials: SH
authors.lastname: Kim
authors.forename: Hye Kyung
authors.initials: HK
authors.lastname: Chung
authors.forename: Joo Hyun
authors.initials: JH
authors.lastname: Kang
authors.forename: Kwang Il
authors.initials: KI
authors.lastname: Kim
authors.forename: Yong Hyun
authors.initials: YH
authors.lastname: Jeon
authors.forename: Yong Nan
authors.initials: YN
authors.lastname: Jin
authors.forename: Chae Ok
authors.initials: CO
authors.lastname: Yun
authors.forename: June-Key
authors.initials: JK
authors.lastname: Chung
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D008114:Liver Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000532:radiotherapy / Q000628:therapy; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012516:Osteosarcoma / Q000000981:diagnostic imaging / Q000532:radiotherapy / Q000628:therapy; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic; D011877:Radionuclide Imaging; D012190:Retroviridae / Q000235:genetics; D027981:Symporters / Q000235:genetics*; D019098:Telomerase / Q000235:genetics*; D014162:Transfection; D014183:Transplantation, Heterologous; D000099209:Sodium-Iodide Symporters
chemical_list: D007457:Iodine Radioisotopes; D027981:Symporters; D019098:Telomerase; D000099209:Sodium-Iodide Symporters; C509186:TERT protein, human