AFP promoter enhancer increased specific expression of the human sodium iodide symporter (hNIS) for targeted radioiodine therapy of hepatocellular carcinoma.
The sodium iodide symporter (NIS) present in the membranes of thyroid cells is responsible for the capacity of the thyroid to concentrate iodide. This allows treatment of thyroid cancers with (131)I. We propose to enlarge the therapeutic strategy to hepatocellular carcinomas by using hepatoma-specific promoter and enhancer for targeted radiotherapy. We constructed a recombinant adenovirus encoding hNIS gene under the control of AFP promoter and enhancer (AdPLEN). After being infected with AdPLEN, HepG2 cells (high AFP-expression hepatoma cells) showed 6 times greater perchlorate-sensitive (125)I uptake than did SMMC7721 cells (low/no AFP-expression hepatoma cells), 30 times higher than Hela (human cervix tumor cells), and noninfected HepG2 cells. These results demonstrate that the AdPLEN vector can function in high AFP expression hepatoma cells. In addition, AdPLEN-infected tumor cells were selectively killed by exposure to (131)I, as revealed by clonogenic assays. To assess the efficiency of this target gene therapy strategy in vivo, we injected the AdPLEN vector in human tumors (HepG2 cells) established in nude mice. Western blotting analysis confirmed the expression of the NIS protein in the tumor. Two days after intratumoral injection, AdPLEN-treated tumors could specifically accumulate (131)I, as revealed by imaging experiments. Altogether, these data indicate that AdPLEN is very efficient in triggering and enlarging significant iodide uptake by hepatocellular carcinomas, outlining the potential of this novel cancer gene therapy approach for a targeted radiotherapy.
Ma
Xiao-Juan
XJ
Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Huang
Rui
R
Kuang
An-Ren
AR
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001692:Biological Transport; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000532:radiotherapy; D002470:Cell Survival; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000532:radiotherapy; D008156:Luciferases / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010472:Perchlorates / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D027981:Symporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D023041:Xenograft Model Antitumor Assays; D000509:alpha-Fetoproteins / Q000235:genetics*; D000099209:Sodium-Iodide Symporters
D007457:Iodine Radioisotopes; D008156:Luciferases; D010472:Perchlorates; D027981:Symporters; D000509:alpha-Fetoproteins; D000099209:Sodium-Iodide Symporters; C097353:AFP protein, human; C494474:perchlorate