In its early stages, malignant melanoma can be cured by surgical resection, but once it has progressed to the metastatic stage it does not respond to current therapies. Therefore, the development of novel treatment strategies, such as gene therapy, is urgently needed. To investigate an alternative approach, we examined the feasibility of NIS-mediated radionuclide therapy (131I, 188Re) of malignant melanoma following human sodium iodide symporter (NIS) gene transfer using a melanoma-specific tyrosinase-promoter construct to target NIS expression to melanoma cells. For this purpose, a human melanoma cell line (Lu1205) was stably transfected with hNIS cDNA under the control of the tyrosinase-promoter. The stably transfected Lu1205 cell line showed perchlorate-sensitive iodide uptake activity which was sufficiently high for a therapeutic effect of 131I as shown in an in vitro clonogenic assay. After injection of 18.5 MBq, 123I NIS-transfected Lu1205 xenografts in nude mice accumulated approximately 30% ID/g 123I with a biological half-life of approximately 11.1 h and an effective half-life of 10.5 h. In comparison, tumoral accumulation of 188Re, which is also transported by NIS, was 15%ID/g with a biological half-life of approximately 15 h and an effective half-life of 8.2 h. After administration of a therapeutic dose of 55.5 MBq, 131I or 188Re NIS-expressing tumors showed an average tumor volume reduction of approx. 50 and 20%, respectively, while control tumors continued their rapid growth exponentially.
In conclusion, a significant therapeutic effect of 131I and 188Re has been demonstrated in melanoma cells following tyrosinase-promoter-directed NIS gene transfer in vitro and in vivo with higher efficacy of 131I. This study demonstrates the potential of NIS-mediated radionuclide therapy of melanoma following tumor-specific NIS gene transfer offering an innovative strategy for melanoma therapy.
03 - 07 May 2008
European Society of Endocrinology