title: Thymidine kinase-mediated killing of rat brain tumors.
abstract: Gene therapy has many potential applications in central nervous system (CNS) disorders, including the selective killing of tumor cells in the brain. A rat brain tumor model was used to test the herpes simplex virus (HSV)-thymidine kinase (TK) gene for its ability to selectively kill C6 and 9L tumor cells in the brain following systemic administration of the nucleoside analog ganciclovir. The HSV-TK gene was introduced in vitro into tumor cells (C6-TK and 9L-TK), then these modified tumor cells were evaluated for their sensitivity to cell killing by ganciclovir. In a dose-response assay, both C6-TK and 9L-TK cells were 100 times more sensitive to killing by ganciclovir (median lethal dose: C6-TK, 0.1 microgram ganciclovir/ml; C6, 5.0 micrograms ganciclovir/ml) than unmodified wild-type tumor cells or cultured fibroblasts. In vivo studies confirmed the ability of intraperitoneal ganciclovir administration to kill established brain tumors in rats as quantified by both stereological assessment of brain tumor volumes and studies of animal survival over 90 days. Rats with brain tumors established by intracerebral injection of wild-type or HSV-TK modified tumor cells or by a combination of wild-type and HSV-TK-modified cells were studied with and without ganciclovir treatments. Stereological methods determined that ganciclovir treatment eliminated tumors composed of HSV-TK-modified cells while control tumors grew as expected (p < 0.001). In survival studies, all 10 rats with 9L-TK tumors treated with ganciclovir survived 90 days while all untreated rats died within 25 days. Curiously, tumors composed of combinations of 9L and 9L-TK cells could be eliminated by ganciclovir treatments even when only one-half of the tumor cells carried the HSV-TK gene. While not completely understood, this additional tumor cell killing appears to be both tumor selective and local in nature. It is concluded that HSV-TK gene therapy with ganciclovir treatment does selectively kill tumor cells in the brain and has many potential applications in CNS disorders, including the treatment of cancer.
authors.affiliation: Department of Surgery, School of Medicine, University of California, San Diego.
authors.forename: D
authors.initials: D
authors.lastname: Barba
authors.forename: J
authors.initials: J
authors.lastname: Hardin
authors.forename: J
authors.initials: J
authors.lastname: Ray
authors.forename: F H
authors.initials: FH
authors.lastname: Gage
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000628:therapy*; D004273:DNA, Neoplasm / Q000187:drug effects; D015774:Ganciclovir / Q000627:therapeutic use*; D015316:Genetic Therapy; D005910:Glioma / Q000628:therapy*; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D018139:Simplexvirus / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D004273:DNA, Neoplasm; D013937:Thymidine Kinase; D015774:Ganciclovir