Iodide kinetics and dosimetry in vivo after transfer of the human sodium iodide symporter gene in rat thyroid carcinoma cells.
Transfer of the human sodium iodide symporter (hNIS) has been proposed as a new principle of cancer gene therapy. This study evaluates the iodide kinetics and dosimetry of iodide in hNIS-expressing thyroid carcinoma cells under optimized conditions.


METHODS
Using a bicistronic retroviral vector for the transfer of the hNIS and the hygromycin resistance gene, hNIS-expressing rat thyroid carcinoma cell lines were generated. Afterward, Na(125)I uptake and efflux were determined in genetically modified and wild-type cells in the presence or absence of modulators of iodide transport. In addition, the (131)I distribution in thyroid-ablated nude mice bearing wild-type and genetically modified thyroid carcinomas was monitored after intraperitoneal administration of (131)I with and without coadministration of lithium carbonate.


RESULTS
hNIS-expressing cell lines accumulated up to 49 times more iodide than did noninfected cells, with a maximal iodide uptake after 30 min of incubation. However, a 90% efflux of the radioactivity occurred 20 min after replacement of the medium. In mice, the hNIS-expressing tumors accumulated up to 23 and 19.5 times more iodide than did the wild-type tumors in lithium-treated and control animals, respectively. However, efflux of the radioactivity was also observed in vivo: After 24 h, hNIS-expressing tumors lost 82.5% and 80.4% of the initial activity. Dosimetric calculations showed that 1,650 MBq of (131)I per square meter resulted in 5.4 and 5.2 Gy in hNIS-expressing tumors and 0.24 and 0.26 in wild-type tumors.


CONCLUSIONS
Transduction of the hNIS gene in rat thyroid carcinoma cells induces iodide transport, which is associated with rapid efflux. Application of (131)I in clinically relevant amounts did not result in therapeutically useful absorbed doses in hNIS-expressing tumors in vivo, even under optimized conditions of thyroid ablation and treatment with lithium carbonate.
Haberkorn
Uwe
U
Department of Nuclear Medicine, University of Heidelberg, Heidelberg, Germany. Uwe.Haberkorn@med.uni-heidelberg.de
Beuter
Petra
P
Kübler
Wolfgang
W
Eskerski
Helmut
H
Eisenhut
Michael
M
Kinscherf
Ralf
R
Zitzmann
Sabine
S
Strauss
Ludwig G
LG
Dimitrakopoulou-Strauss
Antonia
A
Altmann
Annette
A
D000818:Animals; D002291:Carcinoma, Papillary / Q000532:radiotherapy* / Q000628:therapy; D025141:Drug Resistance, Fungal / Q000235:genetics; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D006921:Hygromycin B / Q000494:pharmacology; D007454:Iodides / Q000378:metabolism*; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D016651:Lithium Carbonate / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D011829:Radiation Dosage; D051381:Rats; D012190:Retroviridae; D012974:Sodium Iodide / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D027981:Symporters / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000532:radiotherapy* / Q000628:therapy; D014407:Tumor Cells, Cultured; D000099209:Sodium-Iodide Symporters
D006921:Hygromycin B; D007454:Iodides; D007457:Iodine Radioisotopes; D016651:Lithium Carbonate; D012974:Sodium Iodide; D027981:Symporters; D000099209:Sodium-Iodide Symporters