title: Alpha-fetoprotein promoter-targeted sodium iodide symporter gene therapy of hepatocellular carcinoma.
abstract: Due to limited treatment options the prognosis of patients with advanced hepatocellular cancer (HCC) has remained poor. To investigate an alternative therapeutic approach, we examined the feasibility of radioiodine therapy of HCC following human sodium iodide symporter (NIS) gene transfer using a mouse alpha-fetoprotein (AFP) promoter construct to target NIS expression to HCC cells. For this purpose, the murine Hepa 1-6 and the human HepG2 hepatoma cell lines were stably transfected with NIS cDNA under the control of the tumor-specific AFP promoter. The stably transfected Hepa 1-6 cell line showed a 10-fold increase in iodide accumulation, while HepG2 cells accumulated (125)I approximately 60-fold. Tumor-specific NIS expression was confirmed on mRNA level by northern blot analysis, and on protein level by immunostaining, that revealed primarily membrane-associated NIS-specific immunoreactivity. In an in vitro clonogenic assay up to 78% of NIS-transfected Hepa 1-6 and 93% of HepG2 cells were killed by (131)I exposure, while up to 96% of control cells survived. In vivo NIS-transfected HepG2 xenografts accumulated 15% of the total (123)I administered per gram tumor with a biological half-life of 8.38 h, resulting in a tumor absorbed dose of 171 mGy MBq(-1) (131)I. After administration of a therapeutic (131)I dose (55.5 MBq) tumor growth of NIS expressing HepG2 xenografts was significantly inhibited. In conclusion, tumor-specific iodide accumulation was induced in HCC cells by AFP promoter-directed NIS expression in vitro and in vivo, which was sufficiently high to allow a therapeutic effect of (131)I. This study demonstrates the potential of tumor-specific NIS gene therapy as an innovative treatment strategy for HCC.
authors.affiliation: Department of Internal Medicine II, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: M J
authors.initials: MJ
authors.lastname: Willhauck
authors.forename: B R
authors.initials: BR
authors.lastname: Sharif Samani
authors.forename: K
authors.initials: K
authors.lastname: Klutz
authors.forename: N
authors.initials: N
authors.lastname: Cengic
authors.forename: I
authors.initials: I
authors.lastname: Wolf
authors.forename: L
authors.initials: L
authors.lastname: Mohr
authors.forename: M
authors.initials: M
authors.lastname: Geissler
authors.forename: R
authors.initials: R
authors.lastname: Senekowitsch-Schmidtke
authors.forename: B
authors.initials: B
authors.lastname: Göke
authors.forename: J C
authors.initials: JC
authors.lastname: Morris
authors.forename: C
authors.initials: C
authors.lastname: Spitzweg
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000628:therapy*; D003131:Combined Modality Therapy; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000628:therapy*; D051379:Mice; D011401:Promoter Regions, Genetic; D019275:Radiopharmaceuticals / Q000627:therapeutic use; D027981:Symporters / Q000235:genetics*; D014162:Transfection / Q000379:methods; D000509:alpha-Fetoproteins / Q000235:genetics*; D000099209:Sodium-Iodide Symporters
chemical_list: D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D027981:Symporters; D000509:alpha-Fetoproteins; D000099209:Sodium-Iodide Symporters