S. Cao et al., 5-ETHYNYLURACIL (776C85) - EFFECTS ON THE ANTITUMOR-ACTIVITY AND PHARMACOKINETICS OF TEGAFUR, A PRODRUG OF 5-FLUOROURACIL, Cancer research, 55(24), 1995, pp. 6227-6230
We studied the effects of 5-ethynyluracil (776C85 and 776C), a potent
mechanism-based inactivator of dihydropyrimidine dehydrogenase, on the
antitumor efficacy and pharmacokinetics of tegafur (FT), a prodrug of
5-fluorouracil (5-FU), in rats with large s.c. colon carcinoma, Rats
were dosed p.o. once daily for 7 days with either FT, FT and uracil in
a 1:4 molar ratio (UFT), FT 1 h after 776C (776C/PT), or UFT 1 h afte
r 776C (776C/UFT), 776C, which was dosed at 1 mg/kg, had neither intri
nsic antitumor activity nor toxicity, The rank order in antitumor effi
cacy at the maximal tolerated dose of the FT (mg/kg/day) component was
776C/FT (5 mg/kg/day) greater than or equal to UFT (80 mg/kg/day) = 7
76C/UFT (5 mg/kg/ day) much greater than FT (200 mg/kg/day). One-hundr
ed % of rats treated with 776C/FT had complete and sustained tumor reg
ression with no severe toxicity. The area under the plasma 5-FU concen
tration versus the time curve generated from UFT, FT, and 776C/FT at t
heir maximum tolerated dose was 140, 50, and 27 mu M . h, respectively
. The area under the concentration in plasma versus time curve did not
correlate with the rank order of antitumor efficacy, The vast majorit
y of 5-FU derived from FT (alone) appeared to be rapidly catabolized,
Furthermore, plasma exposure of 5-FU derived from UFT was more variabl
e than that from 776C/FT. Each therapy also produced different levels
of plasma uracil, Endogenous plasma uracil levels (1-3 mu M) were not
affected by FT but increased to 100 mu M after dosing with 776C, Plasm
a uracil from UFT was 800 mu M 1 h after dosing, These results suggest
that moderately elevated uracil (776C/FT) may be beneficial, whereas
uracil that is greatly elevated during the first 5 h (UFT) and 5-FU ca
tabolites (FT alone) may interfere with antitumor efficacy, 776C, coad
ministered with FT, could provide once-a-day oral therapy for cancer p
atients.