The antitumor mechanism of 1-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl)-cytosine: Effects of its triphosphate on mammalian DNA polymerases

Citation
S. Miura et al., The antitumor mechanism of 1-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl)-cytosine: Effects of its triphosphate on mammalian DNA polymerases, JPN J CANC, 92(5), 2001, pp. 562-567
Citations number
22
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
JAPANESE JOURNAL OF CANCER RESEARCH
ISSN journal
0910-5050 → ACNP
Volume
92
Issue
5
Year of publication
2001
Pages
562 - 567
Database
ISI
SICI code
0910-5050(200105)92:5<562:TAMO1>2.0.ZU;2-2
Abstract
The mechanism of action of the antitumor nucleoside analog 1-(2-deoxy-2-flu oro-4-thio-beta -D-arabinofuranosyl)cytosine (4 ' -thio-FAC) was investigat ed. 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 a, whereas it showed mo derate inhibition of DNA polymerase P and little inhibition of DNA polymera se gamma, The kinetic analysis showed that the inhibition mode of 4 ' -thio -FACTP towards DNA polymerase alpha was mixed type, implying a chain-termin ating effect of 4 ' -thio-FACTP, The triphosphate of 2 ' -deoxy-2 ' ,2 ' -d ifluorocytidine (gemcitabine), a known antitumor nucleoside, did not show p otent inhibition of these three DNA polymerases. Thus, the effect of the di phosphate of gemcitabine on ribonucleotide reductase was suggested to be mo re important for the antitumor action of gemcitabine. From these findings, the main target enzymes of 4 ' -thio-FAC and gemcitabine appear to be diffe rent, We found a synergistic effect of the two drugs in an in vitro model, which supports the above idea.