Ectopic expression of the thyroperoxidase gene augments radioiodide uptakeand retention mediated by the sodium iodide symporter in non-small cell lung cancer

Radioiodide is an effective therapy for thyroid cancer. This treatment moda lity exploits the thyroid-specific expression of the sodium iodide symporte r (NIS) gene, which allows rapid internalization of iodide into thyroid cel ls. To test whether a similar treatment strategy could be exploited in nont hyroid malignancies, we transfected non-small cell lung cancer (NSCLC) cell lines with the NIS gene. Although the expression of NIS allowed significan t radioiodide uptake in the transfected NSCLC cell lines, rapid radioiodide efflux limited tumor cell killing. Because thyroperoxidase (TPO) catalyzes iodination of proteins and subsequently Causes iodide retention within thy roid cells, we hypothesized that coexpression of both NIS and TPO genes wou ld overcome this deficiency. Our results show that transfection of NSCLC ce lls with both human NIS and TPO genes resulted in an increase in radioiodid e uptake and retention and enhanced tumor cell apoptosis. These findings su ggest that single gene therapy with only the NIS gene may have limited effi cacy because of rapid efflux of radioiodide. In contrast, the combination o f NIS and TPO gene transfer, with resulting TPO-mediated organification and intracellular retention of radioiodide, may lead to more effective tumor c ell death. Thus, TPO could be used as a therapeutic strategy to enhance the NIS-based radioiodide concentrator gene therapy for locally advanced lung cancer.