Adenovirus-mediated transfer of the thyroid sodium/iodide symporter gene into tumors for a targeted radiotherapy

The Na+/I- symporter (NIS) present in the membranes of thyroid cells is res ponsible for the capacity of the thyroid to concentrate iodide, This allows treatment of thyroid cancers with I-131, We propose to enlarge this therap eutic strategy to nonthyroid tumors by using an adenoviral vector to delive r the NIS gene into the tumor cells, We constructed a recombinant adenoviru s encoding the rat NIS gene under the control of the cytomegalovirus promot er (AdNIS). Infection of SiHa cells (human cervix tumor cells) with AdNIS r esulted in perchlorate-sensitive I-125 uptake by these cells to a level 125 -225 times higher than that in noninfected cells. Similar results were obta ined for other human tumor cell lines, including MCF7 and T-47D (mammary gl and), DU 145 and PC-3 (prostate), A549 (lung), and HT-29 (colon), demonstra ting that the AdNIS vector can function in tumor cells of various origins, In addition, AdNIS-infected tumor cells a ere selectively killed by exposur e to I-131, as revealed by clonogenic assays, To assess the efficiency of t his cancer gene therapy strategy in vivo, we injected the AdNIS vector in h uman tumors (SiHa or MCF7 cells) established s.c. in nude mice, Immunohisto logical analysis confirmed the expression of the NIS protein in the tumor. Three days after intratumoral injection, AdNIS-treated tumors could specifi cally accumulate I-125 Or I-123, as revealed by kinetics and imaging experi ments. A quantitative analysis demonstrated that the uptake in AdNIS-inject ed tumors was 4-25 times higher than that in nontreated tumors. On average, 11% of the total amount of injected I-125 could be recovered per gram of A dNIS-treated tumor tissue. Altogether, these data indicate that AdNIS is ve ry efficient in triggering significant iodide uptake by a tumor, outlining the potential of this novel cancer gene therapy approach for a targeted rad iotherapy.