Christine Spitzweg

In vivo sodium iodide symporter gene therapy of prostate cancer

Radioiodine therapy, the most effective form of systemic radiotherapy available, is currently useful only for thyroid cancer because of thyroid-specific expression of the sodium iodide symporter (NIS). Here we explore the efficacy of a novel form of gene therapy using adenovirus-mediated in vivo NIS gene transfer followed by 131I administration for treatment of prostate cancer. Prostate cancer xenografts in nude mice injected with an adenovirus carrying the NIS gene linked to the cytomegalovirus (CMV) promoter revealed highly active uptake of radioiodine. Following administration of 3 mCi of 131I, we observed an average tumor volume reduction of 84 ± 12%. These results show for the first time that in vivo NIS gene delivery into non-thyroidal tumors is capable of inducing accumulation of therapeutically effective radioiodine doses and might therefore represent an effective and potentially curative therapy for prostate cancer.

Cloning of the mouse sodium iodide symporter.

The iodide-concentrating ability of the thyroid gland is essential to the production of thyroid hormone. We report the nucleotide and amino acid sequence of the mouse sodium iodide symporter (mNIS), which mediates this activity within the thyroid gland. An open reading frame of 1,857 nucleotides codes for a protein of 618 amino acids with 95% identity to rat NIS and 84% identity to human NIS. Transient expression of the mNIS cDNA in Chinese hamster ovary (CHO) cells, a nonthyroid cell line, resulted in sodium-dependent, perchlorate-sensitive iodide uptake. Western blot analysis of membrane preparations of CHO cells transiently transfected with mNIS cDNA showed a band of 90 kd when probed with an antibody directed against rat NIS. mNIS will serve as an important reagent in determining the role of NIS in experimental thyroid diseases and for monitoring the immune response to in animal models of NIS-mediated gene therapy.

THE IMMUNE RESPONSE TO THE IODIDE TRANSPORTER

In addition to physiologic, diagnostic, and therapeutic implications, the recently cloned and characterized sodium iodide symporter (NIS) also may play an important role in the pathogenesis of autoimmune thyroid disease. Sodium iodide symporter expression patterns characteristically are changed in autoimmune thyroid disease, including Graves disease and Hashimotos thyroiditis, which may be caused, in part, by the regulation of sodium iodide symporter expression of cytokines involved in the pathogenesis of autoimmune thyroid disease. Further, there is increasing evidence that NIS-directed antibodies are present in sera from patients with autoimmune thyroid disease, and these antibodies also may affect NIS functional activity.

Sodium iodide symporter: Its biology, clinical relevance, and potential role in the pathophysiology of autoimmune thyroid disease

As the thyroidal membrane protein that mediates iodide transport into thyroidal follicular cells, sodium iodide symporter plays a key role in thyroid pathophysiology and allows effective use of radioiodine for diagnosis and therapy of thyroid cancer. Because of the critical role sodium iodide symporter plays in thyroid function, its potential role as a novel thyroid autoantigen in the pathogenesis of autoimmune thyroid disease has become the focus of many studies. Recent reports involving large series of patient samples and specific and quantitative binding assays were unable to confirm early, promising data that suggested a pathogenic role of sodium iodide symporter in autoimmune thyroid disease. On the other hand, although further studies are needed to determine the clinical importance of sodium iodide symporter as a thyroidal autoantigen, sodium iodide symporter expression detected in mammary glands may have important diagnostic and therapeutic implications in breast cancer. One of the most exciting and promising chapters of sodium iodide symporter gene-based research since its cloning in 1996 is the characterization and application of sodium iodide symporter as a novel therapeutic gene for cytoreductive gene therapy based on targeted sodium iodide symporter gene transfer followed by radioiodine therapy for nonthyroid malignancies.