title: 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.
authors.affiliation: Department of Liver Cancer and Molecular Virology, Institut National de la Santé et de la Recherche Médicale Unit 370, Paris V University, CHU Necker, Paris, France. faivre@necker.fr
authors.forename: Jamila
authors.initials: J
authors.lastname: Faivre
authors.forename: Jérôme
authors.initials: J
authors.lastname: Clerc
authors.forename: René
authors.initials: R
authors.lastname: Gérolami
authors.forename: Julie
authors.initials: J
authors.lastname: Hervé
authors.forename: Michèle
authors.initials: M
authors.lastname: Longuet
authors.forename: Bingkai
authors.initials: B
authors.lastname: Liu
authors.forename: Jérôme
authors.initials: J
authors.lastname: Roux
authors.forename: Frédéric
authors.initials: F
authors.lastname: Moal
authors.forename: Michel
authors.initials: M
authors.lastname: Perricaudet
authors.forename: Christian
authors.initials: C
authors.lastname: Bréchot
mesh_terms: D000818:Animals; D015316:Genetic Therapy; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008099:Liver / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000532:radiotherapy*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D027981:Symporters / Q000235:genetics*; D000099209:Sodium-Iodide Symporters
chemical_list: D007457:Iodine Radioisotopes; D027981:Symporters; D000099209:Sodium-Iodide Symporters