BYSTANDER EFFECT-MEDIATED THERAPY OF EXPERIMENTAL BRAIN-TUMOR BY GENETICALLY-ENGINEERED TUMOR-CELLS

Transfer of the herpes simplex virus-thymidine kinase (HSV-tk) gene, f ollowed by administration of ganciclovir (GCV), generates the ''bystan der 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 w ild-type tumor and then administered GCV, Wild-type 9L-gliosarcoma cel ls (1 x 10(5)) were implanted into the brain of syngeneic Fisher rats, On the next day, rats were injected with TK cells (1 x 10(5) or 3 x 1 0(5)) or medium alone at the same brain coordinate and then treated wi th GCV or saline, Administration of GCV significantly prolonged the su rvival 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 result s show that the bystander effect is also achieved in vivo even when TK cells and wild-type cells are not simultaneously implanted, This trea tment modality circumvents potential risks accompanied with in vivo ge ne transfer, Because there remained substantially no HSV-tk-positive c ells in the recurrent tumors, this modality offers a ''safe'' therapeu tic strategy against human malignant gliomas.