Sodium iodide symporter-based strategy for treatment of thyroid and nonthyroid malignancy.

摘要

The Na+/I− symporter (NIS) is a membrane protein mediating iodide uptake in thyrocytes. It can be upregulated by thyrotropin and facilitates 131I uptake in differentiated thyroid cancers (DTC) to ablate the tumors. Therefore, it has been proposed that NIS expression in surgical samples may serve as a predictor for effectiveness of 131I therapy in DTC. However, its predictive value can be compromised by the difference in serum thyrotropin levels between when surgical samples are obtained and when radioactive iodine uptake (RAIU) is measured. To address this issue, we performed ex vivo thyrotropin-stimulated tissue culture from surgical samples and found that thyrotropin-stimulated NIS mRNA expression showed a better correlation with thyrotropin-induced RAIU, as compared to NIS mRNA expression in surgical samples. Thus, thyrotropin-stimulated NIS expression may be a useful predictor of thyrotropininduced RAIU in thyroid cancers.; Non-thyroid malignancies can also benefit from NIS-mediated radionuclide therapy, provided that NIS can be expressed and functioning in the tumors. We demonstrated exogenous NIS-mediated RAIU in tumors by imaging of the intracerebral NIS-expressing gliomas and by ex vivo tissue counting. A significant difference of RAIU in tumors versus in normal tissues was noted. Despite a short radioiodine retention-time in NIS-expressing gliomas, 131I treatment was able to enhance the survival of rats carrying NIS-expressing gliomas. The therapeutic efficacy of 131I is dose-dependent and intervention time-dependent. The therapeutic effectiveness was further supported by the finding that life spans of 131I-treated rats bearing NIS-expressing gliomas was inversely related to the remaining NIS-expressing cells in tumors. Finally, we investigated the usefulness of 125I and 188ReO₄ in treating rats bearing NIS-transduced gliomas. Both 188ReO₄ and combined 131I/ 125I therapy were more effective than 131I alone in prolonging survival time of rats carrying NIS-transduced gliomas.; In conclusion, ex vivo TSH-stimulated NIS expression is useful to predict TSH-induced RAIU in thyroid cancers. For non-thyroid cancers, NIS gene transfer renders the tumor sensitive to 131I treatment. The therapeutic effectiveness of NIS-mediated radionuclide therapy can be further optimized by adjustment of intervention time and the use of alternative NIS substrates with potent irradiation.