5-Ethynyluracil (776C85) : effects on the antitumor activity and pharmacokinetics of tegafur, a prodrug of 5-fluorouracil
Cao, S.; Baccanari, D.P.; Joyner, S.S.; Davis, S.T.; Rustum, Y.M.; Spector, T.
Cancer Research 55(24): 6227-6230
1995
ISSN/ISBN: 0008-5472 PMID: 8521418 Document Number: 452640
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/FT), or UFT 1 h after 776C (776C/UFT). 776C, which was dosed at 1 mg/kg, had neither intrinsic antitumor activity nor toxicity. The rank order in antitumor efficacy at the maximal tolerated dose of the FT (mg/kg/day) component was 776C/FT (5 mg/kg/day) gtoreq UFT (80 mg/kg/day) = 776C/UFT (5 mg/kg/ day) mchgt FT (200 mg/kg/day). One-hundred % of rats treated with 776C/FT had complete and sustained tumor regression with no severe toxicity. The area under the plasma 5-FU concentration versus the time curve generated from UFT, FT, and 776C/FT at their maximum tolerated dose was 140, 50, and 27 mu-M cntdot h, respectively. The area under the concentration in plasma versus time curve did not correlate with the rank order of antitumor efficacy. The vast majority of 5-FU derived from FT (alone) appeared to be rapidly catabolized. Furthermore, plasma exposure of 5-FU derived from UFT was more variable 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. Plasma 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 catabolites (FT alone) may interfere with antitumor efficacy. 776C, coadministered with FT, could provide once-a-day oral therapy for cancer patients.