5-Fluorocytosine-mediated apoptosis and DNA damage in glioma cells engineered to express cytosine deaminase and their enhancement with interferon.
To explore the antitumor mechanism of bacterial cytosine deaminase plus 5-fluorocytosine (CD/5-FCyt) in combination with interferons (IFNs), glioma cells were transduced with recombinant retroviruses expressing CD. The transduced glioma cells become sensitive to the nontoxic prodrug 5-FCyt. Apoptosis, DNA damage, bystander effect, and inhibition of thymidylate synthase (TS) and DNA synthesis are associated with CD/5-FCyt-mediated glioma cell killing. Furthermore, IFNs enhance this effect by increasing DNA damage and further inhibiting TS activity. The bystander effect is mediated by the release of cytotoxic metabolites of 5-FCyt into the extracellular milieu triggering apoptosis and DNA damage. Our data indicate that the use of CD/5-FCyt in combination with IFNs may provide a more effective approach for the treatment of brain tumors.
Wang
Z H
ZH
Department of Neurology, New York University School of Medicine, New York 10016, USA.
Samuels
S
S
Gama Sosa
M A
MA
Kolodny
E H
EH
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D043525:Cytosine Deaminase; D004247:DNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004249:DNA Damage / Q000187:drug effects*; D004357:Drug Synergism; D005437:Flucytosine / Q000494:pharmacology*; D005910:Glioma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D007372:Interferons / Q000494:pharmacology*; D051379:Mice; D009700:Nucleoside Deaminases / Q000096:biosynthesis* / Q000235:genetics* / Q000494:pharmacology; D051381:Rats; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014162:Transfection; D014407:Tumor Cells, Cultured
D004247:DNA; D007372:Interferons; D005437:Flucytosine; D013940:Thymidylate Synthase; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase