α-fetoprotein promoter-targeted sodium iodide symporter gene therapy of hepatocellular carcinoma

被引：64

作者：

Willhauck, M. J. ^{[1
]}

Samani, B. R. Sharif ^{[1
]}

Klutz, K. ^{[1
]}

Cengic, N. ^{[1
]}

Wolf, I. ^{[2
]}

Mohr, L. ^{[3
]}

Geissler, M. ^{[3
]}

Senekowitsch-Schmidtke, R. ^{[2
]}

Goeke, B. ^{[1
]}

Morris, J. C. ^{[4
]}

Spitzweg, C. ^{[1
]}

机构：

[1] Univ Munich, Klinikum Grosshadern, Dept Internal Med 2, Med Klin 2, D-81377 Munich, Germany

[2] Tech Univ Munich, Dept Nucl Med, Munich, Germany

[3] Univ Freiburg, Dept Internal Med 2, D-7800 Freiburg, Germany

[4] Mayo Clin, Coll Med, Div Endocrinol, Rochester, MN USA

来源：

GENE THERAPY | 2008年 / 15卷 / 03期

关键词：

sodium iodide symporter; hepatocellular carcinoma; alpha-fetoprotein promoter; radioiodine therapy;

D O I：

10.1038/sj.gt.3303057

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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)vertical bar 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)vertical bar exposure, while up to 96% of control cells survived. In vivo NIS-transfected HepG2 xenografts accumulated 15% of the total 123 vertical bar 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)vertical bar. After administration of a therapeutic (131)vertical bar 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)vertical bar. This study demonstrates the potential of tumor-specific NIS gene therapy as an innovative treatment strategy for HCC.

引用

页码：214 / 223

页数：10