Reestablishment ofIn VitroandIn VivoIodide Uptake by Transfection of the Human Sodium Iodide Symporter (hNIS) in a hNIS Defective Human Thyroid Carcinoma Cell Line

Abstract

Uptake of iodide is a prerequisite for radioiodine therapy in thyroid cancer. However, loss of iodide uptake is frequently observed in metastasized thyroid cancer, which may be explained by diminished expression of the human sodium iodide symporter (hNIS). Strategies to restore iodide uptake in thyroid cancer include the exploration of hNIS gene transfer into hNIS defective thyroid cancer. In this study, we report the stable transfection of a hNIS expression vector into the hNIS defective follicular thyroid carcinoma cell line FTC133. Stablely transfected colonies exhibited high uptake of Na125I, which could be blocked completely with sodiumperchlorate. hNIS mRNA expression corresponded with iodide uptake in semiquantitative polymerase chain reaction. Iodide uptake was maximal after 60 minutes, whereas iodide efflux was complete after 120 minutes. hNIS transfected FTC133 and control cell lines injected subcutaneously in nude mice formed tumors after 6 weeks. Iodide uptake in the hNIS transfected tumor was much higher than in the nontransfected tumor, which corresponded with hNIS mRNA expression in tumors.

Enhanced iodide transport after transfer of the human sodium iodide symporter gene is associated with lack of retention and low absorbed dose

“…NIS gene transfer resulted in a high uptake in a variety of tumor models. [8][9][10][11][12][13][14][15][16][17][18][19][20] In the rat prostate carcinoma we observed an up to 200-fold increased uptake as compared to the wild-type cell line which is similar to values reported in other models. 8,10,12,13 However, as observed in a previous study with a rat hepatoma a rapid efflux occurred with 81% of the radioactivity released into the medium after 20 min.…”

“…Similar data have been obtained by other groups in different tumor models. 12,15,17,18,21 Since the effectiveness of radioiodine therapy depends not only on the type and amount, but also on the biological half-life of the isotope in the tumor, a therapeutically useful absorbed dose seems unlikely for that type of experiments.…”

“…[17][18][19][20] In a mouse, doses of 74 and 111 MBq correspond to administered doses of 11 100 and 16 650 MBq/m 2 , respectively. This is far more than the doses used in patients.…”

“…[1][2][3][4][5] Since the cloning of the human and rat cDNA sequences several experimental studies have been performed, which investigated the recombinant expression of the hNIS gene in malignant tumors by viral transfer of the hNIS gene under the control of different promoter elements. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Although all of them reported high initial uptake in the genetically modified tumors, differing results have been obtained concerning the efficiency of radioiodine treatment based on NIS gene transfer with generally very high doses given to tumorbearing mice. In this study, we used the gene for the human sodium-iodide symporter as a paradigm for the genetically modified uptake of 131 I in a rat prostate carcinoma model, and evaluated the iodide uptake kinetics and dosimetry after doses that are commonly administered to patients.…”

Radioiodine therapy of colon cancer following tissue-specific sodium iodide symporter gene transfer

“…Using various gene delivery techniques, including electroporation, liposomes and viral vectors, radioiodine accumulation was induced in vitro and in vivo in various cancer cell lines by NIS gene delivery. [19][20][21][22][23][24][25][26][27][28][29][30] To achieve the ultimate goals of cancer therapy, which are maximal tissue-or tumor-specific cytotoxicity with a minimum of toxic effects in nonmalignant cells, as well as elimination of metastatic cancer cells in addition to the local tumor, tissue-or tumor-specific targeting of therapeutic genes is desirable. Besides the possibility of surface targeting by viral vector envelope modification or modification of the viral backbone to generate viral vectors that selectively replicate in tumor cells, the application of tissue-or tumor-specific promoters provides a well-established way of transcriptionally targeting of therapeutic genes selectively to cancer cells.…”