Image-Guided Radioiodide Therapy of Medullary Thyroid Cancer After Carcinoembryonic Antigen Promoter-Targeted Sodium Iodide Symporter Gene Expression

Abstract

In contrast to follicular cell-derived thyroid cancer, medullary thyroid cancer (MTC) remains difficult to treat because of its unresponsiveness to radioiodine therapy, or to conventional chemo- and radiotherapy. We therefore examined the feasibility of radioiodine therapy of MTC after human sodium iodide symporter (hNIS) gene transfer, using the tumor-specific carcinoembryonic antigen (CEA) promoter for transcriptional targeting. NIS gene transfer was performed in vivo in human MTC cell (TT) xenografts, using adenoviral vectors carrying the NIS gene linked to the cytomegalovirus promoter (Ad5-CMV-NIS) or a CEA promoter fragment (Ad5-CEA-NIS). Functional NIS expression was confirmed by immunostaining as well as in vivo ¹²³I γ-camera imaging followed by application of a therapeutic ¹³¹I dose. TT cell xenografts in nude mice injected intratumorally with Ad5-CEA-NIS accumulated 7.5 ± 1.2% ID/g (percentage injected dose per gram tumor tissue; 5 × 10⁸ PFU) and 12 ± 2.95% ID/g (1 × 10⁹ PFU) with an average biological half-life of 6.1 ± 0.8 and 23.6 ± 3.7 hr, respectively, as compared with accumulation of 8.4 ± 0.9% ID/g with a biological half-life of 12 ± 8 hr after application of Ad5-CMV-NIS (5 × 10⁸ PFU). After Ad5-CEA-NIS-mediated NIS gene transfer in TT cell xenografts administration of a therapeutic dose of 111 MBq (3 mCi) of ¹³¹I resulted in a significant reduction of tumor growth associated with significantly lower calcitonin serum levels in treated mice as well as improved survival. We conclude that a therapeutic effect of ¹³¹I was demonstrated in vivo in MTC cell xenografts after adenovirus-mediated induction of tumor-specific iodide accumulation by CEA promoter-directed hNIS expression.