Bystander Effect-Mediated Therapy of Experimental Brain Tumor by Genetically Engineered Tumor Cells

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Abstract
Transfer of the herpes simplex virus-thymidine kinase (HSV-tk) gene, followed by administration of ganciclovir (GCV), generates the “bystander effect,” in which HSV-tk-negative wild-type cells, as well as HSV-tk-expressing cells, are killed by GCV. To eradicate an intracranial tumor by this bystander effect, we injected the tumor cells transduced with the HSV-tk gene (TK cells) in the vicinity of the preimplanted wild-type tumor and then administered GCV. Wild-type 9L-gliosarcoma cells (1 × 105) were implanted into the brain of syngeneic Fisher rats. On the next day, rats were injected with TK cells (1 × 105 or 3 × 105) or medium alone at the same brain coordinate and then treated with GCV or saline. Administration of GCV significantly prolonged the survival of the rats injected with TK cells compared with that injected with medium alone (p < 0.01). Reduction in tumor size and retardation of tumor growth were observed by serial magnetic resonance imaging in the rats that received the combination of TK cells and GCV. The results show that the bystander effect is also achieved in vivo even when TK cells and wild-type cells are not simultaneously implanted. This treatment modality circumvents potential risks accompanied with in vivo gene transfer. Because there remained substantially no HSV-tk-positive cells in the recurrent tumors, this modality offers a “safe” therapeutic strategy against human malignant gliomas. The “bystander” killing of neighboring wild-type tumor cells has been observed in a suicide gene therapy using the herpes simplex virus-thymidine kinase (HSV-tk) gene and the antiviral agent ganciclovir (GCV). This paper introduces a therapeutic approach for the treatment of brain tumors by generating the “bystander effect” associated with HSV-tk/GCV system. Wild-type 9L-gliosarcoma cells implanted in the rat brain were treated with the combination of subsequent injection of HSV tk-transduced 9L cells in the vicinity of the preimplanted wild-type tumor and intraperitoneal GCV administration. Significant prolongation of survival and retardation of tumor growth were observed in the treated rats. The present study shows an alternative approach of HSV-tk/GCV gene therapy without using in vivo gene transfer.

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