Radioiodine gene therapy of hepatocellular carcinoma targeted human alpha fetoprotein.
BACKGROUND
We conducted a molecular imaging and gene therapy method in alpha-fetoprotein (AFP)-producing hepatocellular carcinoma (HCC) by tumor-specific expression of the human sodium/iodide symporter (hNIS) using an AFP promoter.


METHODS
The tumor-specific expression of hNIS gene by the AFP enhancer/promoter was constructed as pcDNA3-AFP/hNIS. The pcDNA3-AFP/hNIS was stably transfected to human HCC (Huh-7/AN) and rat glioma cells (C6/AN). Functional hNIS expression was confirmed by radioiodine uptake. The mRNA and protein-expression level of hNIS were measured. Biodistribution of 131I was evaluated, and scintigraphic images of 99mTc were obtained in xenografted mice. A clonogenic assay was performed by 131I. And, the in vivo therapeutic effect of 131I was evaluated in xenografted mice.


RESULTS
In Huh-7/AN cells, iodine was highly accumulated and completely blocked by perchlorate. The protein and mRNA expression levels were correlated with iodine uptake. Radioiodine uptake in Huh-7/AN tumors was higher than those of control tumors and clearly visualized. The survival rate was significantly decreased in Huh-7/AN cells by 131I. Moreover, a growth of Huh-7/AN tumors was inhibited by 131I in mice.


CONCLUSIONS
AFP-producing hepatoma can be targeted and treated with radionuclides and hNIS, using AFP enhancer/promoter. This targeted hNIS gene therapy and molecular imaging have the potential to be used in the management of AFP-producing HCC.
Jin
Yong Nan
YN
Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea.
Chung
Hye Kyung
HK
Kang
Joo Hyun
JH
Lee
Yong Jin
YJ
Kimm
Kwang Il
KI
Kim
Young Joo
YJ
Kim
Seunghoo
S
Chung
June-Key
JK
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000532:radiotherapy* / Q000628:therapy*; D045744:Cell Line, Tumor; D004742:Enhancer Elements, Genetic; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007457:Iodine Radioisotopes / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000532:radiotherapy* / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D051381:Rats; D013667:Technetium / Q000378:metabolism; D000509:alpha-Fetoproteins / Q000096:biosynthesis*
D007457:Iodine Radioisotopes; D000509:alpha-Fetoproteins; D013667:Technetium