α-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 a-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

Antitumor potential of SLPI promoter controlled recombinant caspase-3 expression in laryngeal carcinoma

“…4,15,16 In the current study, the transcription efficiency of SLPIb promoter (À650 to þ 22) was the highest among all candidate promoters in laryngeal carcinoma Hep-2 cell but very low in human vein endothelial cell HUVEC and osteosarcoma MG-63 cells, indicating this SLPIb promoter was an efficient and tissue-specific promoter for human laryngeal squamous cell carcinoma cell line Hep-2. As no targeted gene therapy for laryngeal carcinoma has been investigated before, this is the first attempt in this area with this strategy.…”

The Biology of the Sodium Iodide Symporter and its Potential for Targeted Gene Delivery

“…We do not have human studies of exogenous NIS gene transfer for direct comparison. However, in the study by performed in adult male beagle dogs, the average absorbed-dose delivered to the prostate following intraprostatic injection of 1 × 10 12 viral particles of Ad-CMV-NIS was estimated to be much lower at 0.23 ± 0.42 Gy after an intravenous administration of 1 (37 MBq) mCi 131 I [153]. The therapeutic effect observed in this situation is mediated by radioiodide-induced lethal and sublethal cellular DNA damage, which primarily depends on the area under the curve of the cumulative radioactivity within the cell.…”

“…Furthermore, this correlated with a reduced level of NIS protein expression on western blot analysis [134]. Most subsequent studies have employed low-iodine diets combined with T4 supplementation (0.05-5 mg/l) for 1-2 weeks prior to radioiodide therapy [128,[150][151][152][153]. The effectiveness and feasibility of using this protocol can be gauged from the study by Wapnir et al (2004) that was performed in patients with metastatic breast cancer [109].…”

“…No major toxicities or changes in blood biochemistries were noted. This was the first study of its kind to assess the reporter and possible therapeutic functions of NIS-mediated radioisotope therapy in large animals that involved administration of therapeutic doses of I similar to those used in the clinical setting [153].…”

“…Most commonly, NIS gene expression has been mapped using pertechnetate ( 99m TcO 4 − )-or iodide ( 123 I)-based scintigraphic techniques with conventional gamma camera imaging [138,[150][151][152] or SPECT/CT [153]. Scintigraphic assessment enables estimation of the level of radioisotope uptake and the effective half-life within the NIS-transduced tumour, which may then be employed to provide reliable estimates of the tumour absorbed dose.…”