Tumour-specific activation of the sodium/iodide symporter gene under control of the glucose transporter gene 1 promoter (GTI-1.3).
Targeted transfer of a functionally active sodium iodide symporter (NIS) into tumour cells may be used for radioiodine therapy of cancer. Therefore, we investigated radioiodine uptake in a hepatoma cell line in vitro and in vivo after transfer of the sodium iodide symporter ( hNIS) gene under the control of a tumour-specific regulatory element, the promoter of the glucose transporter 1 gene (GTI-1.3). Employing a self-inactivating bicistronic retroviral vector for the transfer of the hNIS and the hygromycin resistance genes, rat Morris hepatoma (MH3924A) cells were infected with retroviral particles and hNIS-expressing cell lines were generated by hygromycin selection. (125)I(-) uptake and efflux were determined in genetically modified and wild type hepatoma cells. In addition, the iodide distribution in rats bearing wild type and genetically modified hepatomas was monitored. hNIS-expressing MH3924A cell lines accumulated up to 30 times more iodide than wild type hepatoma cells, with a maximal iodide uptake after 30 min incubation time. Competition experiments in the presence of sodium perchlorate revealed a decrease in the iodide uptake (80-84% decrease). Moreover, ouabain led to a loss of accumulated I(-) (81% decrease) whereas 4,4'-diisothiocyano-2,2'-disulphonic acid stilbene (DIDS) increased the I(-) uptake into cells (87% increase). However, a rapid efflux of the radioactivity (70%) was observed 20 min after (125)I(-)-containing medium had been replaced by non-radioactive medium. Lithium had no significant effect on iodide efflux. In rats, the hNIS-expressing tumours accumulated 22 times more iodide than the contralateral wild type tumour. In accordance with the in vitro data, we also observed a rapid efflux of the radioactivity out of the tumour in vivo. Dosimetric calculations resulted in an absorbed dose of 85 mGy in the wild type tumour and 830 mGy in the hNIS-expressing tumour after administration of 18.5 MBq (131)I. In conclusion, transduction of the hNIS gene under the control of the GLUT1 promoter element induces iodide transport in Morris hepatoma cells in vitro and in vivo. However, for therapeutic application additional conditions need to be defined which inhibit the iodide efflux out of the tumour cells.
Sieger
Stephanie
S
Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Centre, Heidelberg, Germany.
Jiang
Shiming
S
Schönsiegel
Frank
F
Eskerski
Helmut
H
Kübler
Wolfgang
W
Altmann
Annette
A
Haberkorn
Uwe
U
D000818:Animals; D001693:Biological Transport, Active; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D051272:Glucose Transporter Type 1; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D009928:Organ Specificity; D011401:Promoter Regions, Genetic / Q000235:genetics; D011829:Radiation Dosage; D011874:Radiometry / Q000379:methods; D051381:Rats; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014161:Transduction, Genetic / Q000379:methods*; D000099209:Sodium-Iodide Symporters
D051272:Glucose Transporter Type 1; D007457:Iodine Radioisotopes; D009004:Monosaccharide Transport Proteins; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C495679:Slc2a1 protein, rat