Linked Life Data

8521418

Source:http://linkedlifedata.com/resource/pubmed/id/8521418

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
24
pubmed:dateCreated
1996-1-22
pubmed:abstractText
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) > or = UFT (80 mg/kg/day) = 776C/UFT (5 mg/kg/day) >> 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 microM.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 microM) were not affected by FT but increased to 100 microM after dosing with 776C. Plasma uracil from UFT was 800 microM 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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
55
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
6227-30
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1995
pubmed:articleTitle
5-Ethynyluracil (776C85): effects on the antitumor activity and pharmacokinetics of tegafur, a prodrug of 5-fluorouracil.
pubmed:affiliation
Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't