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
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.