A novel therapeutic strategy for medullary thyroid cancer based on radioiodine therapy following tissue-specific sodium iodide symporter gene expression.
BACKGROUND
In contrast to papillary and follicular thyroid cancer, medullary thyroid cancer (MTC) remains difficult to treat due to its unresponsiveness to radioiodine therapy and its limited responsiveness to chemo- and radiotherapy.


OBJECTIVE
To investigate an alternative therapeutic approach, we examined the feasibility of radioiodine therapy of MTC after human sodium iodide symporter (hNIS) gene transfer using the calcitonin promoter to target hNIS gene expression to MTC cells (TT).


METHODS
TT cells were stably transfected with an expression vector, in which hNIS cDNA was coupled to the calcitonin promoter. Functional hNIS expression was confirmed by iodide accumulation assays, Northern and Western blot analysis, immunostaining, and in vitro clonogenic assay.


RESULTS
hNIS-transfected TT cells showed perchlorate-sensitive iodide uptake, accumulating 125-I about 12-fold in vitro with organification of 4% of accumulated iodide resulting in a significant decrease in iodide efflux. NIS protein expression was confirmed by Western blot analysis using a monoclonal hNIS-specific antibody, which revealed a major band of a molecular mass of 80-90 kDa. In addition, immunostaining of hNIS-transfected TT cells revealed hNIS-specific immunoreactivity, which was primarily membrane associated. In an in vitro clonogenic assay, 84% of NIS-transfected TT cells were killed by exposure to 131-I, whereas only about 0.6% of control cells were killed.


CONCLUSIONS
A therapeutic effect of 131-I has been demonstrated in MTC cells after induction of tissue-specific iodide uptake activity by calcitonin promoter-directed hNIS expression. This study demonstrates the potential of NIS as a therapeutic gene, allowing radioiodine therapy of MTC after tissue-specific NIS gene transfer.
Cengic
Neziha
N
Department of Internal Medicine II, Klinikum Grosshadern, Ludwig-Maximilians-University, 81377 Munich, Germany.
Baker
Claire H
CH
Schütz
Martin
M
Göke
Burkhard
B
Morris
John C
JC
Spitzweg
Christine
C
D015152:Blotting, Northern; D015153:Blotting, Western; D001943:Breast Neoplasms; D002116:Calcitonin / Q000235:genetics; D018276:Carcinoma, Medullary / Q000235:genetics / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D018076:DNA, Complementary; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007454:Iodides / Q000493:pharmacokinetics; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D011401:Promoter Regions, Genetic / Q000235:genetics; D027981:Symporters / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000532:radiotherapy*; D014162:Transfection; D000099209:Sodium-Iodide Symporters
D002116:Calcitonin; D018076:DNA, Complementary; D007454:Iodides; D007457:Iodine Radioisotopes; D027981:Symporters; D000099209:Sodium-Iodide Symporters