Although xenotransplantation of retrovirus-producing cells longed survival periods were observed. When mice were into a tumor has been shown to be effective for the treattreated with repeated intratumoral injections of HSVtk-carment of cancer, injections of recombinant retroviruses are rying retrovirus-producing cells, significant antitumor much more feasible for clinical applications. We estabresponses and some cures were induced by GCV treatlished a clone producing retroviruses carrying the herpes ment. Furthermore, repeated intratumoral injections of simplex virus thymidine kinase (HSVtk) gene with titers of HSVtk-carrying retroviruses and GCV treatment resulted in up to 4 × 10 7 colony-forming units/ml, and examined the complete regression of established HCC tumors in all anieffectiveness of in vivo gene therapy against cancer. Synmals used in the experiment. Mice that completely eradigeneic mice were inoculated subcutaneously with murine cated tumors exhibited protective immunity against wildhepatocellular carcinoma (HCC) cells, BNL1ME A.7R.1, type HCC tumors. These results suggest that repeated and the treatment was initiated after tumors were estabinjections of HSVtk-carrying retroviruses followed by GCV lished. When mice were given an intratumoral injection of treatment is a potent modality for the treatment of solid HSVtk-carrying retroviruses or their producing cells foltumors. lowed by ganciclovir (GCV) treatment, significantly pro-

Although adenovirus is an attractive vehicle for transferring although intraportal infusion of adenoviruses carrying a therapeutic genes in vivo, animal studies have indicated reporter lacZ gene resulted in transient high levels of transthat the clinical usefulness of adenoviruses may be limited gene expression in the rat liver, intraportal readministration by their immunogenicity. Although immunosuppressive of adenoviruses failed to induce detectable levels of transstrategies around the time of initial exposure of adenogene expression. Conversely, when animals were treated viruses have been shown to prevent the formation of neutransiently with cyclophosphamide before the intraportal tralizing antibodies and permit the successful readminisreadministration of adenoviruses, development of neutration of adenoviruses in animals, the practicality of the tralizing antibodies and antigen-specific T cell proliferation approaches remains questionable. Because the majority of in response to adenoviral readministration was significantly prospective gene therapy patients have already been suppressed and successful re-expression of the transgene infected with wild-type adenoviruses, initial treatment with was achievable. These results may have important impliadenoviruses in humans may correspond to readminiscations for efficacy considerations when adenoviral vectors tration of adenoviruses into animals. It is shown here that are employed in clinical settings.

Background-When recombinant adenoviruses are infused directly into the circulation, transgene expression is almost completely restricted to the liver. Aims-EYciency and safety of adenovirus mediated gene transfer into damaged livers were examined in mice with liver cirrhosis or fulminant hepatitis. Methods-Liver cirrhosis and fulminant hepatitis were induced by intraperitoneal administration of thioacetamide and D-galactosamine followed by lipopolysaccharide, respectively. Mice were infused with adenoviruses carrying the Escherichia coli -galactosidase gene, lacZ gene, into the tail vein. Transduction eYciency of the lacZ gene was estimated histochemically by X-gal staining and quantitatively using a chemiluminescent assay. Activation of adenovirus specific T cells and development of neutralising antibodies against adenovirus were also examined. Results-Histochemical evaluation revealed that approximately 40%, 80%, and 40% of cells in normal, cirrhotic, and fulminant hepatitis livers, respectively, were stained blue using X-gal staining. Quantitative analyses revealed that levels of lacZ expression in cirrhotic livers were approximately 2.5-fold and sixfold greater than those in normal and fulminant hepatitis livers, respectively. Although transgene expression in fulminant hepatitis livers was significantly lower than that in normal livers, marked levels of transgene expression were achieved even in fulminant hepatitis livers. Significant adverse eVects of adenoviruses were not observed in damaged livers. There were no significant diVerences in cellular or humoral immune responses to adenoviruses among animals with normal, cirrhotic, and fulminant hepatitis livers. Conclusions-Our results suggest that gene therapy with adenoviruses may be used eYciently and safely, even in patients with severe liver disease.

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