Gene therapy has many potential applications in central nervous system
(CNS) disorders, including the selective killing of tumor cells in th
e brain. A rat brain tumor model was used to test the herpes simplex v
irus (HSV)-thymidine kinase (TK) gene for its ability to selectively k
ill C6 and 9L tumor cells in the brain following systemic administrati
on of the nucleoside analog ganciclovir. The HSV-TK gene was introduce
d in vitro into tumor cells (C6-TK and 9L-TK), then these modified tum
or cells were evaluated for their sensitivity to cell killing by ganci
clovir. 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 mug ganciclovir/ml; C6, 5.0 mug ganciclovir/ml) than unmodifi
ed wild-type tumor cells or cultured fibroblasts. In vivo studies conf
irmed the ability of intraperitoneal ganciclovir administration to kil
l 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 injectio
n of wild-type or HSV-TK modified tumor cells or by a combination of w
ild-type and HSV-TK-modified cells were studied with and without ganci
clovir treatments. Stereological methods determined that ganciclovir t
reatment eliminated tumors composed of HSV-TK-modified cells while con
trol 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. lt is
concluded that HSV-TK gene therapy with ganciclovir treatment does sel
ectively kill tumor cells in the brain and has many potential applicat
ions in CNS disorders, including the treatment of cancer.