Bystander effect-mediated suicide gene therapy of experimental brain tumor by genetically engineered tumor cells in rat

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Our previous study demonstrated that intracranial 9L glioma could be efficiently treated due to the bystander effect by injecting the 9L glioma cells transduced with herpes simplex virus-thymidine kinase(HSVtk)gene(9Ltk)in the vicinity of the preimplanted wild-type 9L glioma and then administerin ganciclovir(GCV)(TK cell therapy). For a possible clinical application of the bystander effect-mediated cell killing, we tested HSVtk gene trransduced allogeneic C6 glioma(C6tk)cells instead of 9Ltk(allogeneic TK cell therapy). Intracranial 9L glioma could also be efficiently treated by allogeneic TK cell therapy, though this bystander effect was weaker than syngeneic TK cell therapy. Since allogeneic tumor cells are finally rejected, the allogeneic TK cell therapy is a safe and feasible strategy for glioma treatment.The bystander effect between different tumor cell lines(9L and C6 cells)was then studied using mixed populations of wild-type cells(9Lwt and C6wt)and respective TK cells(9Ltk and C6tk). A potent in vitro bystander effect was observed in 9Lwt/9Ltk and 9Lwt/C6tk combinations but not in C6wt/9Ltk and C6wt/C6tk combinations. In vivo bystander effect studied in a subcutaneous tumor model in athymic nude mice was also potent in 9Lwt/9Ltk and 9Lwt/C6tk combinations. Since the expression of connexin43, a major protein in the connexin family gene products, in 9L cells is much higher than that in C6 cells, the results suggest that the amount of connexin in target wild-type cells but not in effector TK cells is important for the generation of the bystander effect. This hypothesis was further confirmed by the observation that in vitro bystander effect in C6wt/C6tk combination was potentiated by transduction of the connexin43 gene to the target cells