Viral vector transduction of the human deoxycytidine kinase cDNA sensitizes glioma cells to the cytotoxic effects of cytosine arabinoside in vitro and in vivo.
Cytosine arabinoside (ara-C) is a cytidine analog that incorporates into replicating DNA and induces lethal DNA strand breaks. Although ara-C is a potent antitumor agent for hematologic malignancies, it has only minimal activity against most solid tumors. The rate-limiting step in intracellular ara-C activation is phosphorylation of the prodrug by deoxycytidine kinase (dCK). The present results demonstrate that both retroviral and adenoviral vector-mediated transduction of the dCK cDNA results in marked sensitization of glioma cells lines to the cytotoxic effects of ara-C in vitro. We also demonstrate that ara-C treatment of established intradermal and intracerebral gliomas transduced with dCK results in significant antitumor effects in vivo. These data suggest that viral vector transduction of the dCK gene followed by treatment with ara-C represents a new chemosensitization strategy for cancer gene therapy.
Manome
Y
Y
Division of Cancer Pharmacology, Dana Farber Cancer Institute, Boston, Massachusetts, USA.
Wen
P Y
PY
Dong
Y
Y
Tanaka
T
T
Mitchell
B S
BS
Kufe
D W
DW
Fine
H A
HA
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D003561:Cytarabine / Q000378:metabolism / Q000494:pharmacology*; D003842:Deoxycytidine Kinase / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005822:Genetic Vectors; D018316:Gliosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D014162:Transfection
D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D003561:Cytarabine; D003842:Deoxycytidine Kinase