Gene Therapy (2002) 9, 1139–1145  2002 Nature Publishing Group All rights reserved 0969-7128/02 $25.00 www.nature.com/gt RESEARCH ARTICLE In vivo imaging and radioiodine therapy following sodium iodide symporter gene transfer in animal model of intracerebral gliomas J-Y Cho 1 , DHY Shen 1 , W Yang 2 , B Williams 3 , TLF Buckwalter 1 , KMD La Perle 4 , G Hinkle 3 , R Pozderac 3 , R Kloos 5 , HN Nagaraja 6 , RF Barth 2 and SM Jhiang 1 1 Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA; 2 Department of Pathology, The Ohio State University, Columbus, OH, USA; 3 Department of Radiology, The Ohio State University, Columbus, OH, USA; 4 Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA; 5 Department of Internal Medicine, The Ohio State University, Columbus, OH, USA; and 6 Department of Statistics, The Ohio State University, Columbus, OH, USA Radioactive iodide uptake (RAIU) in thyroid follicular epi- thelial cells, mediated by the sodium iodide symporter (NIS), is the first rate-limiting step in iodide accumulation which pro- vides a mechanism for effective radioiodide treatment for patients with thyroid cancer. We hypothesize that NIS gene transfer to non-thyroid tumor cells will enhance intracellular radioiodide accumulation and result in better tumor control. Here, we performed non-invasive tumor imaging and 131 I therapy studies using rats bearing intracerebral F98 gliomas that have been retrovirally transduced with human NIS. Our results show that: (1) NIS is expressed in the intracerebral F98/NIS gliomas; (2) F98/NIS gliomas can be imaged by Keywords: sodium/iodide symporter; radionuclide imaging; gene therapy; recombinant retrovirus; thyroid; brain neoplasm Introduction Iodine is an essential component of thyroid hormone. Since iodine is a rare element, the thyroid gland has an effective way to sequester iodine from blood circulation for the synthesis of thyroid hormones. The iodide uptake activity in thyroidal follicular cells is mediated by sodium iodide symporter (NIS), which is an intrinsic membrane protein with 13 putative transmembrane domains. 1–3 Electrophysiological studies revealed that NIS transports one I - ion with two Na + ions into cells. 4 Animal studies and clinical observations showed that NIS-expressing tissues could also concentrate pertechnetate (TcO 4 - ), 5 perrhenate (ReO 4 - ), 5,6 and astatide (At - ). 7,8 NIS is expressed primarily in thyroid tissues, but variable degrees of NIS expression were observed in various tissues including nasal mucosa, stomach, salivary glands, and lactating breast tissues. Radioiodide concentrating activity in the thyroid has provided a mechanism for imaging and treatment by spe- cific radionuclides for patients with thyroid cancers after Correspondence: SM Jhiang, Department of Physiology and Cell Biology, The Ohio State University, 304 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210-1218, USA The first two authors contributed equally to this paper Received 17 January 2002; accepted 13 April 2002 99 mTcO 4 (whose uptake is also mediated by NIS) and 123 I scintigraphy; (3) significant amounts of radioiodide were retained in the tumors at 24 h after 123 I injection; (4) RAIU and NIS expression in the thyroid gland can be reduced by feeding a thyroxine-supplemented diet; and (5) survival time was increased in rats bearing F98/hNIS tumors by 131 I treat- ment. These studies warrant further investigating tumor imaging and therapeutic strategies based on NIS gene transfer followed by radioiodide administration in a variety of human cancers. Gene Therapy (2002) 9, 1139–1145. doi:10.1038/sj.gt.3301787 thyroidectomy. Following molecular cloning of NIS, 1,2 we and others demonstrated that active iodide uptake can be induced in a variety of cells by NIS gene transfer using transient 1,9 or stable transfection. 9,10 Based on these obser- vations, we hypothesized that efficient NIS gene transfer to tumor cells will allow intracellular radioiodide accumulation following radioiodide administration, and thereby result in better tumor control. To test this hypothesis, we previously studied the expression and activity of human NIS (hNIS) in cultured human glioma cells by adenovirus-mediated gene deliv- ery in vitro and in vivo. 11 Delivery of exogenous hNIS in vitro resulted in more than a 120-fold increase of RAIU in U1240 cells infected with recombinant adenovirus car- rying hNIS, compared with parental cells. Intratumoral injection of rAd-CMV-hNIS into subcutaneous xenografts of U251 human gliomas resulted in an approximately 25- fold increase of 125 I accumulation over the spleen or saline-injected tumors. 11 Similarly, other investigators have also reported that either retrovirus- or adenovirus- mediated gene delivery of NIS to various human cancer cell lines resulted in increased radioiodide uptake activity in cultured cells, as well as in vivo imaging of xenografts expressing exogenous NIS. 12,13 In addition, enhanced tumor-killing effects of 131 I after NIS gene transfer have been demonstrated by in vitro clonogenic assays 12,14 and by decreased tumor volume in nude mice carrying xeno-