In the field of gene therapy using retroviral vectors, it appears impossible to introduce a foreign gene into all target cells. Therefore adjacent cell killing, the socalled bystander effect, caused by genetically modified cells provides therapeutic advantages for gene therapy against cancers. We retrovirally transduced the herpes simplex virus thymidine kinase (HSV-tk) gene into murine and rat hepatocellular carcinoma (HCC) cells. These HSV-tk gene-transduced HCC cells were cocultured with the corresponding parental cells in the presence of ganciclovir, at a concentration not at all cytotoxic to the parental cells. When parental HCC cells were cocultured with their HSV-tk gene-transduced counterparts at a high density at which most cells were in contact with one another, they were markedly eliminated. Conversely, when cocultured at a low density at which none of the cells were in contact, a weak but statistically significant bystander effect was observed. Addition of lysates of HSV-tk gene-transduced cells in the presence of ganciclovir did not cause and killing of parental cells. Furthermore, media conditioned by transduced cells with ganciclovir exhibited weak cytotoxic effects on parental cells. These results indicate that cell-cell contact plays a major causative role in the bystander effect and that minor contributors to this phenomenon are some cytotoxic substance released from transduced cells. Importantly, the bystander effect was induced in vivo as well as in vitro. When mixtures of transduced and untransduced HCC cells were implanted into the flank region of mice, intraperitoneal ganciclovir administration considerably inhibited tumor development, indicating the feasibility of gene therapy with HSV-tk gene and ganciclovir against HCC.
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.
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