The antitumor mechanism of 1-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl)-cytosine: effects of its triphosphate on mammalian DNA polymerases.
The mechanism of action of the antitumor nucleoside analog 1-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl)cytosine (4'-thio-FAC) was investigated. 4'-Thio-FAC inhibited cellular DNA synthesis, but not RNA and protein syntheses. We observed potent inhibitory action of the triphosphate of 4'-thio-FAC (4'-thio-FACTP) against DNA polymerase alpha, whereas it showed moderate inhibition of DNA polymerase beta and little inhibition of DNA polymerase gamma. The kinetic analysis showed that the inhibition mode of 4'-thio-FACTP towards DNA polymerase alpha was mixed type, implying a chain-terminating effect of 4'-thio-FACTP. The triphosphate of 2'-deoxy-2',2'-difluorocytidine (gemcitabine), a known antitumor nucleoside, did not show potent inhibition of these three DNA polymerases. Thus, the effect of the diphosphate of gemcitabine on ribonucleotide reductase was suggested to be more important for the antitumor action of gemcitabine. From these findings, the main target enzymes of 4'-thio-FAC and gemcitabine appear to be different. We found a synergistic effect of the two drugs in an in vitro model, which supports the above idea.
Miura
S
S
Biochemicals Division, Yamasa Corporation, Choshi, Chiba 288-0056, Japan. miura@yamasa.com
Yoshimura
Y
Y
Satoh
H
H
Izuta
S
S
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003561:Cytarabine / Q000031:analogs & derivatives / Q000494:pharmacology*; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004347:Drug Interactions; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007700:Kinetics; D009062:Mouth Neoplasms / Q000473:pathology; D019384:Nucleic Acid Synthesis Inhibitors; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
C114001:1-(2-deoxy-2-fluoro-4-thio-arabinofuranosyl)cytosine; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D003561:Cytarabine; D003841:Deoxycytidine; D004256:DNA Polymerase I; D000093542:Gemcitabine