Treatment of rat experimental brain tumors by herpes simplex virus thymidine kinase gene-transduced allogeneic tumor cells and ganciclovir

Transfer of the herpes simplex virus thymidine kinase (HSVtk) gene, followe d by administration of ganciclovir (GCV), generates the "bystander effect," in which HSVtk-negative wild-type cells are killed by GCV, as are HSVtk-ex pressing cells. Our previous study demonstrated that intracranial 9L glioma s could be efficiently treated due to this bystander effect by injecting th e 9L glioma cells transduced with the HSVtk gene in the vicinity of the pre implanted wild-type 9L glioma and then administering GCV. For a possible cl inical application of the bystander effect-mediated cell killing, we tested HSVtk gene-transduced allogeneic C6 glioma cells (C6tk) instead of syngene ic 9L glioma cells transduced with the HSVtk gene. Fisher rats were implant ed intracranially with wild-type 9L glioma cells, subsequently injected wit h C6tk cells at the same brain coordinate, and thereafter treated with GCV or saline. When the rats were treated with GCV, a significant retardation o f tumor growth was observed by serial magnetic resonance imaging, although this growth retardation was less prominent than that observed with 9L gliom a cells transduced with the HSVtk gene; consequently, survival was prolonge d (P < .01). Tumors that received C6tk cells contained almost no HSVtk-posi tive cells after treatment with GCV, Rejection of allogeneic tumor cells, a lthough possibly incomplete in the brain, can also contribute to the safety of this therapeutic strategy.