Targeted Killing of Migrating Glioma Cells by Injection of HTK-Modified Glioma Cells

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Abstract
The “bystander effect” describes the killing of nearby unmodified cells and herpes simplex thymidine kinase (HTK)-transduced cells by ganciclovir (GCV) treatment. This effect is thought to be produced by contact between these cells. In this study, we showed that injected glioma cells migrated rapidly to a place distant from the injection point whereas injected virus-producing fibroblast cells did not migrate in a murine brain model. Moreover, the initially injected glioma cells and glioma cells injected at a later time mix very well, even at a place distant from the injection point. This suggested that glioma cells migrating after injection could be targeted by HTK-modified glioma cells introduced in a second injection and be killed together by GCV treatment. Therefore, we injected HTK-modified glioma cells 3 days after injection of wild glioma cells to investigate whether wild-type glioma cells that migrated to a place distant from the injection point could also be killed by GCV treatment. Tumor growth was suppressed after the GCV treatment. Suppression of tumor growth of wild glioma cells is not solely mediated by the immune response, which may be triggered by the killing of HTK-modified glioma cells with GCV, because inoculation of HTK-modified glioma to the contralateral side followed by GCV treatment did not cure the initial wild glioma. Moreover, the migration of the second inoculum of glioma cells is necessary for effective killing, because early administration of GCV resulted in insufficient killing. In gene therapy of malignant cells with the herpes simplex thymidine kinase (HTK) gene, the bystander effect is essential for effective killing of tumor cells. This effect is thought to be produced by direct contact between HTK-transduced cells and unmodified malignant cells. We observed rapid migration of injected glioma cells in a murine brain model. This phenomenon is thought to be the main reason why malignant glioma is refractory to treatment. Directly injected virus-producing cells do not migrate in the same manner as glioma cells, so that migrating glioma cells may not be killed with GCV treatment In this study, we showed the usefulness of the injection of HTK-modified glioma followed by GCV treatment for migrating glioma cells. This method should be applicable to human glioma therapy.