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Submitted on October 29, 2004
Accepted on May 26, 2005
Department of Internal Medicine II, Klinikum Grosshadern, Ludwig-Maximilians-University Munich, Germany, Department of Endocrinology, Mayo Clinic, College of Medicine, Rochester, MN 55905, USA
* To whom correspondence should be addressed. E-mail: Christine.Spitzweg{at}med.uni-muenchen.de.
Context: 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 following human sodium iodide symporter (hNIS) gene transfer using the calcitonin promoter to target hNIS gene expression to MTC cells (TT).
Design: 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 weight 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, while only about 0.6% of control cells were killed.
Conclusions: A therapeutic effect of 131-I has been demonstrated in MTC cells following 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 following tissue-specific NIS gene transfer.
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