title: Sodium-iodine symporter gene expression controlled by the EGR-1 promoter: biodistribution, imaging and in vitro radionuclide therapy with Na(131)I.
abstract: The objective of this study is to explore the feasibility of radioiodine treatment for cervical cancer using the early growth response (Egr-1) promoter to control sodium-iodine symporter (hNIS) gene expression. The hNIS gene was previously transfected into Hela cells under the control of either the cytomegalovirus (CMV) or Egr-1 promoters. Na(125)I uptake was measured in the presence or absence of NaClO4. Na(125)I efflux was measured. The effects of external beam radiation on iodine uptake and retention were studied. The cytotoxic effects of (131)I were measured by clonogenic assay. The Na(125)I biodistribution was obtained using mice bearing control and transfected cells. The %ID/g of tumor and major organs were obtained for a range of times up to 48 hours post injection and the ratio of tumor to non-tumor activity (T/NT) was calculated. Tumors were imaged with Na(131)I and (99m)TcO4 (-), and the ratio of tumor to background activity (T/B) was calculated. Na(125)I uptake in Hela cells was minimal in the absence of hNIS. Uptake in the transfected cells was strong, and could be blocked by NaClO4. The iodine uptake of Hela-Egr-1-hNIS cells increased after the irradiation, and the magnitude of this effect approximately matched the radiation dose delivered. The efflux of 125I was affected by neither the promoter sequence nor pre-irradiation. (131)I reduced the clonogenic survival of symporter expressing cells, relative to the parental line. The effect was greatest in cells where hNIS was driven by the CMV promoter. Tumors formed from Hela-Egr-1-hNIS concentrated Na(125)I over a 12 hour period, in contrast to untransfected cells. These tumors could also be successfully imaged using either Na(131)I or (99m)TcO4 (-). (131)I uptake peaked at 4h, while (99m)TcO4 (-) accumulated over approximately 20 hours. In vivo uptake of (131)I and (99m)TcO4 (-) was slightly higher in cells transfected with the Egr-1 promoter, compared to CMV. Hela-Egr-1-hNIS cells demonstrate highly enhanced iodine uptake, and this effect is further augmented by radiation, creating a positive feedback loop which may bolster radionuclide therapy in vivo.
authors.affiliation: Department of Nuclear Medicine, the 2 Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province, P.R. China Jun Tang and Xiaoxia Wang contributed equally to this paper. drtaungjun@aliyun.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Oncology, the 2 Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province, P.R. China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Nuclear Medicine, the 2 Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province, P.R. China.
authors.forename: Yuanqi
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Nuclear Medicine, the 2 Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province, P.R. China.
authors.forename: Yizhen
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Nuclear Medicine, the 2 Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province, P.R. China.
authors.forename: Zengli
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Nuclear Medicine, the 2 Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic; D011877:Radionuclide Imaging; D012974:Sodium Iodide; D027981:Symporters / Q000235:genetics*; D013667:Technetium; D002583:Uterine Cervical Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics / Q000532:radiotherapy; D023041:Xenograft Model Antitumor Assays; D000099209:Sodium-Iodide Symporters
chemical_list: D051766:Early Growth Response Protein 1; D007457:Iodine Radioisotopes; D012974:Sodium Iodide; D027981:Symporters; D013667:Technetium; D000099209:Sodium-Iodide Symporters
keywords: Cervical cancer; Egr-1; NIS; Nude mouse.; Radionuclide therapy