Long-Term Radioiodine Retention and Regression of Liver Cancer after Sodium Iodide Symporter Gene Transfer in Wistar Rats

Abstract

Radioiodine therapy of nonthyroid cancers after sodium iodide symporter (NIS) gene delivery has been proposed as a potential application of gene therapy. However, it seems to be precluded by the rapid efflux of taken up iodine from most transduced xenografted tumors. We present an in vivo kinetic study of NIS-related hepatic iodine uptake in an aggressive model of hepatocarcinoma induced by diethylnitrosamine in immunocompetent Wistar rats. We followed the whole-body iodine distribution by repeated imaging of live animals. We constructed a rat NIS (rNIS) adenoviral vector, Ad-CMV-rNIS, using the cytomegalovirus (CMV) as a promoter. Injected in the portal vein in 5 healthy and 25 hepatocarcinoma-bearing rats and liver tumors in 9 hepatocarcinoma-bearing rats, Ad-CMV-rNIS drove expression of a functional NIS protein by hepatocytes and allowed marked (from 20 to 30% of the injected dose) and sustained (>11 days) iodine uptake. This contrasts with the massive iodine efflux found in vitro in human hepatic tumor cell lines. In vivo specific inhibition of NIS by sodium perchlorate led to a rapid iodine efflux from the liver, indicating that the sustained uptake was not attributable to an active retention mechanism but to permanent recycling of the effluent radioiodine via the high hepatic blood flow. Radioiodine therapy after Ad-CMV-rNIS administration achieved a strong inhibition of tumor growth, the complete regression of small nodules, and prolonged survival of hepatocarcinoma-bearing rats. This demonstrates for the first time the efficacy of NIS-based radiotherapy in a relevant preclinical model of nonthyroid human carcinogenesis.

SPECT/CT imaging of oncolytic adenovirus propagation in tumours in vivo using the Na/I symporter as a reporter gene

“…16 hNIS has been shown to allow accumulation of radioactive iodide endogenously and transduced exogenously expressing tissues for non-invasive imaging [17][18][19][20] and is unlikely to interfere with the cell biochemistry. 21 Different modalities have been reported to image hNISexpressing tissues, including positron emission tomography (PET), [22][23][24] scintigraphic imaging 25 and single photon emission computed tomography (SPECT). 26 The imaging of hNIS-expressing tissues is particularly versatile since hNIS can promote cellular uptake of different radioisotopes 123 I (SPECT), 124 I (PET), 99m Tc (SPECT), 131 I (scintigraphic imaging).…”

“…26 The imaging of hNIS-expressing tissues is particularly versatile since hNIS can promote cellular uptake of different radioisotopes 123 I (SPECT), 124 I (PET), 99m Tc (SPECT), 131 I (scintigraphic imaging). 19,[25][26][27][28] In the present study, we have generated two replication-competent adenoviruses (AdIP1 and AdAM6) encoding the hNIS cDNA. AdIP1 is a 'wild-type' virus based on the Ad-5 serotype in which the only modification is the replacement of the gp19k gene in the E3 region by the hNIS cDNA.…”

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

“…For example, 1200 MBq/m 2 of 131 I was associated with a mean tumour dose (MTD) of 3+/−0.5 Gy (wildtype tumour 0.15+/−0.1 Gy) and 2400 MBq/m 2 with MTD of 3.1+/−0.9 Gy (wild-type tumour 0.26+/−0.02 Gy) [141]. Further to this, Faivre et al (2004) reported on an in vivo kinetic study of NIS-related iodine uptake in an aggressive model of hepatocarcinoma induced by diethylnitrosamine in immunocompetent Wistar rats. An adenoviral vector expressing rNIS regulated by the CMV promoter (Ad-CMV-NIS) was injected into the portal vein of 5 healthy and 25 hepatocarcinoma-bearing rats.…”

“…Similarly, an in vivo therapeutic dose of 131 I (1 mCi) was associated with a delay in the growth of NIS-transduced tumours in athymic nude mice. Moreover, when radioiodide was administered to mice with established xenografts of stably transfected NIS-expressing FaDu cells, almost complete tumour regression was observed [143]. Schipper et al (2005) reported on the results of NIS-mediated radioiodide therapy in a neuroendocrine cancer model.…”

In Vitro Radionuclide Therapy and In Vivo Scintigraphic Imaging of Alpha-Fetoprotein-Producing Hepatocellular Carcinoma by Targeted Sodium Iodide Symporter Gene Expression

“…In the current study, we have used serotype 5 human adenovirus vector because it can infect various human cells easily without any severe side effects, and localize preferentially to the liver when administered intravenously, which suggests that it is suitable for selective HCC treatment [34]. Most studies of targeted NIS gene therapy using tumor specific promoter have been conducted under limited gene delivery condition including the use of stable cell lines established with a retrovirus or plasmid, or local injection of adenovirus vector [30,35,36]. The present study shows the possibility of non-invasive in vivo imaging of tumor-targeted gene expression after intravenous administration of adenovirus.…”