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Treatment with Drugs Able to Reduce Iodine Efflux Significantly Increases the Intracellular Retention Time in Thyroid Cancer Cells Stably Transfected with Sodium Iodide Symporter Complementary Deoxyribonucleic Acid

Department of Endocrinology and Metabolism, Section of Endocrinology (R.E., A.V., R.C., F.S., A.P.); Department of Oncology, Division of Pathology III (P.F., F.B.); and Service of Radiation Safety, South Chiara Hospital (C.T.), University of Pisa, 56124 Pisa, Italy; Department of Internal Medicine, Endocrinology and Metabolism, and Biochemistry, University of Siena (F.P.), 53100 Siena, Italy; and AMBISEN Center, High Technology Center for the Study of the Environmental Damage of the Endocrine and Nervous Systems, University of Pisa (A.P.), 56100 Pisa, Italy

Address all correspondence and requests for reprints to: Dr. Rossella Elisei, Department of Endocrinology and Metabolism, Via Paradisa 2, University of Pisa, 56124 Pisa, Italy. E-mail: relisei{at}endoc.med.unipi.it.

Context: One of the major limits of gene therapy with sodium iodide symporter (NIS), which enables cells to be subjected to radioiodine therapy, is that NIS-transfected cells rapidly release the intracellular iodine.

Methods: We transfected human anaplastic (FRO) and medullary (TT) thyroid cancer-derived cell lines that were unable to take up iodine with human NIS cDNA. The possibility of increasing the iodine retention time by treating the transfected clones with myricetin, lithium, 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) was explored.

Results: We obtained 19 FRO and 16 TT clones stably transfected with NIS. Twelve of 19 FRO and nine of 16 TT clones expressed the full-length NIS mRNA; 11 of 12 FRO and four of nine TT clones were able to take up radioiodine and correctly expressed NIS protein on the plasma membrane. Kinetic analysis of iodide uptake in the two clones (FRO-19 and TT-2) with the highest uptaking activity revealed that the plateau was reached after 30 min by FRO-19 and after 60 min by TT-2. The t_1/2 of the iodide efflux was 9 min in FRO-19 and 20 min in TT-2. The treatment of the two cell lines with four different drugs revealed that DIDS and 17-AAG, but not myricetin and lithium, significantly increased the intracellular iodide retention time in FRO-19, but not in TT-2.

Conclusions: We showed that 17-AAG and DIDS prolong the retention time of ¹³¹I in NIS-transfected thyroid tumoral cells, thus reinforcing the hope of using this approach for future clinical application, especially in patients with thyroid carcinoma who are no longer responsive to conventional therapy.