Establishment of a human hepatocellular carcinoma cell line highly expressing sodium iodide symporter for radionuclide gene therapy.

Abstract

UNLABELLED:

To evaluate the possibility of radionuclide gene therapy and imaging in hepatocellular carcinoma cancer, we investigated the iodine accumulation of a human hepatocellular carcinoma cell line, SK-Hep1, by transfer of human sodium iodide symporter (hNIS) gene. By targeting NIS expression in SK-Hep1, we could also investigate whether these cells concentrate 99mTc-pertechnetate and 188Re-perrhenate as well as 125I in vitro and in vivo.

METHODS:

The hNIS gene was transfected to human hepatocellular carcinoma SK-Hep1 cell lines using lipofectamine plus reagent. The uptake and efflux of 125I, 99mTc-pertechnetate, and 188Re-perrhenate were measured in the transfected and parental cells. Biodistribution was studied in nude mice bearing SK-Hep1 and SK-Hep1-NIS at 10 and 30 min and at 1, 2, 6, 16, and 23 h after injection of 125I, 99mTc- pertechnetate, or 188Re-perrhenate. In tumor imaging studies, the nude mice were intravenously injected with 188Re-perrhenate and imaged with a gamma-camera equipped with a pinhole collimator at 30 and 60 min after injection. The survival rate (%) was determined by the clonogenic assay after 37 MBq/10 mL (1 mCi/10 mL) 131I and 188Re-perrhenate treatment.

RESULTS:

SK-Hep1-NIS, stably expressing the NIS gene, accumulated 125I up 150 times higher than that of SK-Hep1. Iodine uptake of SK-Hep1-NIS is completely blocked by perchlorate. NIS gene transfection into SK-Hep1 also resulted in 112- and 87-fold increases of 99mTc-pertechnetate and 188Re-perrhenate uptake, respectively. Iodide efflux from SK-Hep1-NIS was relatively slow, with only 10% released during the initial 5 min, and 60% remained at 25 min. In the biodistribution study using SK-Hep1-NIS-xenographed mice, the tumor uptake of 125I, 188Re-perrhenate, and 99mTc-pertechnetate was 68.0 +/- 15.0, 46.2 +/- 9.1, and 59.6 +/- 16.2 %ID/g (percentage injected dose per gram) at 2 h after injection, respectively. After 188Re-perrhenate injection in SK-Hep1 and SK-Hep1-NIS-xenographed nude mice, whole-body images clearly visualized the SK-Hep1-NIS tumor, whereas the control tumor was not visualized. The survival rate (%) of SK-Hep1-NIS was markedly reduced to 46.3% +/- 10.1% and 28.9% +/- 5.2% after 37 MBq/mL (1 mCi/10 mL) 131I and 188Re-perrhenate treatment compared with the survival rates of the parental cells. These results demonstrated that SK-Hep1-NIS could be selectively killed by the induced 131I and 188Re-perrhenate accumulation through NIS gene expression.

CONCLUSION:

NIS-based gene therapy using beta-emitting radionuclides has the potential to be used in hepatocellular carcinoma management.

• Authors: Joo Hyun Kang, June-Key Chung, Yong Jin Lee, Jae Hoon Shin, Jae Min Jeong, Dong Soo Lee, Myung Chul Lee
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 45 Issue 9 Pg. 1571-6 (Sep 2004) ISSN: 0161-5505 [Print] United States
• PMID: 15347726 (Publication Type: Comparative Study, Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Radioisotopes
• Radiopharmaceuticals
• Recombinant Proteins
• Symporters
• sodium-iodide symporter

Topics

• Animals
• Carcinoma, Hepatocellular (diagnostic imaging, genetics, metabolism, radiotherapy)
• Cell Line, Tumor
• Combined Modality Therapy
• Genetic Therapy (methods)
• Humans
• Liver Neoplasms (diagnostic imaging, genetics, metabolism, radiotherapy)
• Metabolic Clearance Rate
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Radioisotopes (pharmacokinetics, therapeutic use)
• Radionuclide Imaging
• Radiopharmaceuticals (pharmacokinetics, therapeutic use)
• Recombinant Proteins (genetics, metabolism)
• Symporters (genetics, metabolism)
• Tissue Distribution
• Transfection (methods)
• Treatment Outcome