The glial fibrillary acidic protein promoter directs sodium/iodide symporter gene expression for radioiodine therapy of malignant glioma.

Radioiodine is a routine therapy for differentiated thyroid cancers. Non-thyroid cancers may be treated with radioiodine following transfection with the human sodium/iodide symporter (hNIS) gene. The glial fibrillary acidic protein (GFAP) promoter is an effective tumor-specific promoter for gene expression and thus may be useful in targeted gene therapy of malignant glioma. The present study used GFAP promoter-modulated expression of the hNIS gene in an experimental model of radioiodine-based treatment for malignant glioma. Cells were transfected using a recombination adenovirus and evaluated in cells by studying the transfected transgene expression through western blot analysis, I-125 uptake and efflux, clonogenicity following I-131 treatment and radioiodine therapy using a U87 xenograft nude mouse model. Following transfection with the hNIS gene, the cells showed 95-70-fold higher I-125 uptake compared with the control cells transfected with Ad-cytomegalovirus (CMV)-enhanced green fluorescent protein (EGFP). The western blotting revealed bands of similar to 70, 49 and 43 kDa, consistent with the hNIS, GFAP and beta-actin proteins. The clonogenic assay indicated that, following exposure to 500 mu Ci of I-131-iodide for 12 h, >90% of cells transfected with the hNIS gene were killed. Ad-GFAP-hNIS-transfected and 2 mCi I-131-injected U87 xenograft nude mice survived the longest of the three groups. The hNIS-expressing tumor tissue accumulated (TcO4)-Tc-99m rapidly within 30 min of it being intraperitoneally injected. The experiments demonstrated that effective I-131 therapy was achieved in the malignant glioma cell lines following the induction of tumor-specific iodide uptake activity by GFAP promoter-directed hNIS gene expression in vitro and in vivo. I-131 therapy retarded Ad-GFAP-hNIS transfected-tumor growth following injection with I-131 in U87 xenograft-bearing nude mice.