In vivo and in vitro glioma cell killing induced by an adenovirus expressing both cytosine deaminase and thymidine kinase and its association with interferon-alpha.
An adenovirus, AdCDTK, expressing both bacterial cytosine deaminase (CD) and herpes simplex virus thymidine kinase (HSVTK) was constructed and introduced into glioma cells. AdCDTK selectively rendered glioma cells sensitive to both 5-fluorocytosine (5-FCyt) and ganciclovir (GCV) (termed AdCDTK/5-FCyt-GCV). AdCDTK/5-FCyt-GCV not only potently mediated apoptosis and the arrest of glioma cell growth in vitro, but also significantly increased the survival time of glioma-bearing rats as compared with controls. The 90-day survival time was observed in 50% of rats. Interferon-alpha (IFN-alpha) further enhanced the tumor cell killing of AdCDTK/5-FCyt-GCV. In the group of AdCDTK/5-FCyt-GCV/IFN-alpha, the average survival time was significantly increased, and the average tumor size was smaller than that in the group of AdCDTK/5-FCyt-GCV. Ninety-day survival increased from 50% in the group of AdCDTK/5-FCyt-GCV to 75% in the group of AdCDTK/5-FCyt-GCV/IFN-alpha. Complete tumor regression was observed in 50% of rats in the group of AdCDTK/5-FCyt-GCV/IFN-alpha. The data indicate that AdCDTK/5-FCyt-GCV induces glioma cell killing greater than that induced by either CD/5-FCyt or HSVTK/GCV alone. IFN-alpha synergistically enhances this effect by increasing apoptosis.
Wang
Z H
ZH
Department of Neurology, New York University School of Medicine, New York 10016, USA.
Zagzag
D
D
Zeng
B
B
Kolodny
E H
EH
D000256:Adenoviridae / Q000201:enzymology / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy; D002470:Cell Survival / Q000187:drug effects; D043525:Cytosine Deaminase; D004273:DNA, Neoplasm / Q000096:biosynthesis; D005437:Flucytosine / Q000378:metabolism / Q000494:pharmacology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005910:Glioma / Q000473:pathology* / Q000628:therapy / Q000821:virology; D016898:Interferon-alpha / Q000494:pharmacology*; D008297:Male; D009368:Neoplasm Transplantation; D009700:Nucleoside Deaminases / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000096:biosynthesis*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D016898:Interferon-alpha; D012333:RNA, Messenger; D005437:Flucytosine; D013937:Thymidine Kinase; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase