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Evaluation of HSV-tk Gene Therapy in a Rat Model of Chemically Induced Hepatocellular Carcinoma by Intratumoral and Intrahepatic Artery Routes¹

INSERM U370, Necker Faculty of Medicine, 75730 Paris [R. G., A. S. C., C. B., P-L. T.]; Laboratoire de Recherche en Chirurgie, INSERM 94–05, Hopital Cochin, 75014 Paris [J. C.]; Laboratoire de Recherche en Imagerie, INSERM U494, Necker Faculty of Medicine, 75730 Paris [M. L., O. C.]; and Service d’Anatomie Pathologique, Hopital Beaujon, 92110 Clichy [M-P. B.], France

Transfer of the herpes simplex virus-thymidine kinase (HSV-tk) gene followed by the administration of ganciclovir (GCV) into hepatocellular carcinoma (HCC)-derived cell lines either in vitro or transplanted into nude mice has been shown to provide a potential strategy for HSV-tk-based gene therapy of HCC. We report herein an analysis of the antitumoral efficacy of two recombinant adenoviruses (Ads), Ad.CMVtk and Ad.AFPtk, in a relevant model of multifocal hepatic lesions induced in rats by a potent alkylating chemical carcinogen, diethylnitrosamine. Two routes of administration of the Ad were studied: intratumoral and intrahepatic artery injections. Both recombinant Ads, Ad.CMVtk and Ad.AFPtk, express the HSV-tk gene under the control of the early enhancer/promoter cytomegalovirus and -fetoprotein regulatory gene sequences, respectively. The antitumor response was assessed by magnetic resonance imaging and by autopsy and histological analysis following postmortem. Tumor growth cessation was demonstrated by magnetic resonance imaging in large tumor nodules of size 5–8 mm treated by intratumoral administration of 2 x 10⁹ pfu Ad.CMVtk plus i.p. treatment with GCV. We also show an antitumor efficacy in small tumor nodules of size <3 mm treated with 2 x 10⁹ pfu Ad.CMVtk plus GCV by the intrahepatic artery route, albeit associated with an adverse toxicity. In vivo targeting of the HSV-tk gene to diethylnitrosamine-induced HCC cells with the recombinant Ad.AFPtk suppresses the hepatic toxicity in the nontumoral liver. The lower antitumor response would argue for the use of multiple injections of such adenoviral constructs. These observations may lead to potential approaches for designing gene therapy destined for early treatment of dysplastic nodules or advanced HCC in cirrhosis.

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