DEFECTIVE HERPES-SIMPLEX VIRUS VECTORS EXPRESSING THYMIDINE KINASE FOR THE TREATMENT OF MALIGNANT GLIOMA

Viral vectors used for cancer gene therapy have usually been either re plication-incompetent vectors expressing a gene product that leads to the destruction of the tumor or replication-competent vectors that are inherently cytotoxic to the tumor cells. We have sought to combine th e attributes of these different approaches using a defective herpes si mplex virus (HSV) vector that consists of a defective particle, contai ning tandem repeats of the HSV thymidine kinase (TK) gene, and a repli cation-competent, non-neurovirulent HSV mutant as a helper virus. HSV- TK activity in defective vector-infected cells was significantly great er than that in helper virus-infected cells which contained a single c opy of HSV-TK. infection of cells with this defective vector renders t hem, as well as surrounding uninfected cells, sensitive to killing by ganciclovir. Ganciclovir treatment of C57BL/6 mice bearing TK-defectiv e vector/helper virus-infected subcutaneous GL261 gliomas resulted in significantly decreased tumor size.