Tumour-specific activation of the sodium/iodide symporter gene under control of the glucose transporter gene 1 promoter (GTI-1.3)

Abstract

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 However, a rapid efflux of the radioactivity (70%) was observed 20 min after (125)I(-)-containing medium had been replaced by non-radioactive medium.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.

Combining transfer of TTF-1 and Pax-8 gene: a potential strategy to promote radioiodine therapy of thyroid carcinoma

“…Although the tumors efficiently concentrated iodide after NIS gene transfer, no effect of 131 I on tumor growth was observed because the rapid iodide efflux from the tumor did not allow the delivery of a radiation dose sufficient to inhibit cell growth. 21,31,32 Thus, to efficiently therapy tumor with 131 I by gene transfer, it is mandatory to increase the retention time of iodide in the tumor. An appealing strategy is to mimic the situation existing in the thyroid, that is, to organify the iodide taken up by the tumor.…”

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

“…First experiments in our laboratory showed only a marginal effect of lithium in hNIS-expressing hepatoma cells. 32 A further option to increase therapy outcome is the use of biologically more effective isotopes. Dadachova et al 33 compared 188 Re-perrhenate with 131 I for the treatment of NIS-expressing mammary tumors.…”

The Biology of the Sodium Iodide Symporter and its Potential for Targeted Gene Delivery

“…Furthermore, iodide uptake in a panel of non-prostate tumour cell lines infected with Ad-ARR(2)PB/hNIS was significantly lower, indicating the tissue specificity of this construct [139]. Sieger et al (2003), investigated radioiodide 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 (GT1) gene (GTI-1.3). NIS-expressing stable cell lines (rat hepatoma (MH3924A)) demonstrated perchlorate-sensitive increased iodide uptake (30-fold increase in vitro and 22-fold increase in vivo) compared to the wild-type cell line.…”

“…The authors subsequently demonstrated flattening of the in vivo dose-response curve with increasing 131 I concentration that was attributed to the rapid iodide efflux. For example, 1200 MBq/m 2 of 131 I was associated with a mean tumour dose (MTD) of 3+/−0.5 Gy (wildtype tumour 0.15+/−0.1 Gy) and 2400 MBq/m 2 with MTD of 3.1+/−0.9 Gy (wild-type tumour 0.26+/−0.02 Gy) [141]. Further to this, Faivre et al (2004) reported on an in vivo kinetic study of NIS-related iodine uptake in an aggressive model of hepatocarcinoma induced by diethylnitrosamine in immunocompetent Wistar rats.…”

“…One of the main advantages of NIS gene is its applicability as a reporter gene that may be employed for real-time non-invasive assessment of the biodistribution, gene expression and replication of various vector systems [141]. Most commonly, NIS gene expression has been mapped using pertechnetate ( 99m TcO 4 − )-or iodide ( 123 I)-based scintigraphic techniques with conventional gamma camera imaging [138,[150][151][152] or SPECT/CT [153].…”