Enhanced cytotoxicity of antiviral drugs mediated by adenovirus directed transfer of the herpes simplex virus thymidine kinase gene in rat glioma cells.
The antiviral agents ganciclovir, 1-beta-D-arabinofuranosylthymine (araT), acyclovir, and 5-iodo-5'-amino-2',5'-dideoxyuridine were cytotoxic to rat C6 glioma cells expressing retrovirally transferred herpes simplex virus (HSV) type 1 thymidine kinase (TK) coding sequence, with concentrations that inhibited cell survival by 50% (IC50 values) of 0.06, 3, 13, and 23 mumol/L, respectively. In C6 cells not expressing HSV-TK, the IC50 value for ganciclovir was 140 mumol/L and a concentration of 1 mmol/L killed more than 99% of the cells. The other antiviral agents tested were less toxic in nontransduced cells. Compared with retrovirally transduced cells, transduction of C6BU1 cells with an adenovirus vector containing the coding sequence for HSV-TK (Ad.RSVtk) increased the cellular activity of the viral kinase up to 600-fold with increasing multiplicity of infection (MOl). Cells transduced with Ad.RSVtk exhibited as much as a fivefold and 12-fold decrease in IC50 value for ganciclovir and araT, respectively, compared with retrovirally transduced cells. Sensitivity to antiviral drugs increased with increasing exposure to Ad.RSVtk, with IC50 values of 0.6 and 0.005 mumol/L for araT and ganciclovir, respectively, at an MOl of 1000. These data suggest that adenoviral transfer of HSV-TK will allow the use of less toxic drugs or lower concentrations of toxic drugs such as ganciclovir for directed antitumor therapy in vivo.
Shewach
D S
DS
Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, USA.
Zerbe
L K
LK
Hughes
T L
TL
Roessler
B J
BJ
Breakefield
X O
XO
Davidson
B L
BL
D000212:Acyclovir / Q000378:metabolism / Q000633:toxicity*; D000260:Adenoviruses, Human / Q000235:genetics*; D000818:Animals; D001087:Arabinonucleosides / Q000378:metabolism / Q000633:toxicity*; D001358:Avian Sarcoma Viruses / Q000235:genetics; D001932:Brain Neoplasms / Q000473:pathology*; D004351:Drug Resistance / Q000235:genetics*; D015774:Ganciclovir / Q000378:metabolism / Q000633:toxicity*; D005814:Genes, Viral; D005822:Genetic Vectors; D005910:Glioma / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D013936:Thymidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects
D001087:Arabinonucleosides; D011993:Recombinant Fusion Proteins; D013937:Thymidine Kinase; C010032:thymine arabinoside; D015774:Ganciclovir; D013936:Thymidine; D000212:Acyclovir