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Titolo:
Reduction of 5-fluorouracil (5-FU) gastrointestinal (GI) toxicity resulting from the protection of thymidylate synthase (TS) in GI tissue by repeatedsimultaneous administration of potassium oxonate (Oxo) in rats
Autore:
Yoshisue, K; Hironaga, K; Yamaguchi, S; Yamamoto, A; Nagayama, S; Kawaguchi, Y;
Indirizzi:
Taiho Pharmaceut Co Ltd, Tokushima Res Ctr, Pharmacokinet Res Lab, Kawauchi, Tokushima 7710194, Japan Taiho Pharmaceut Co Ltd Kawauchi Tokushima Japan 7710194 a 7710194, Japan Taiho Pharmaceut Co Ltd, Drug Safety Res Lab, Kawauchi, Tokushima 7710194,Japan Taiho Pharmaceut Co Ltd Kawauchi Tokushima Japan 7710194 ma 7710194,Japan Taiho Pharmaceut Co Ltd, Pharmacol Res Lab, Kawauchi, Tokushima 7710194, Japan Taiho Pharmaceut Co Ltd Kawauchi Tokushima Japan 7710194 a 7710194, Japan
Titolo Testata:
CANCER CHEMOTHERAPY AND PHARMACOLOGY
fascicolo: 1, volume: 46, anno: 2000,
pagine: 51 - 56
SICI:
0344-5704(200007)46:1<51:RO5(G(>2.0.ZU;2-N
Fonte:
ISI
Lingua:
ENG
Soggetto:
CONTINUOUS INFUSION; ANTITUMOR-ACTIVITY; INTESTINAL TOXICITY; LONG-TERM; CARCINOMA; INHIBITION; SYNTHETASE; MECHANISM; ADENOCARCINOMA; PHARMACOLOGY;
Keywords:
S-1; potassium oxonate; thymidylate synthase; gastrointestinal toxicity; ileum;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
27
Recensione:
Indirizzi per estratti:
Indirizzo: Yoshisue, K Taiho Pharmaceut Co Ltd, Tokushima Res Ctr, Pharmacokinet Res Lab, 224-2 Ebisuno, Kawauchi, Tokushima 7710194, Japan Taiho Pharmaceut Co Ltd 224-2 Ebisuno Kawauchi Tokushima Japan 7710194
Citazione:
K. Yoshisue et al., "Reduction of 5-fluorouracil (5-FU) gastrointestinal (GI) toxicity resulting from the protection of thymidylate synthase (TS) in GI tissue by repeatedsimultaneous administration of potassium oxonate (Oxo) in rats", CANC CHEMOT, 46(1), 2000, pp. 51-56

Abstract

Purpose: An important cytotoxic effect of 5-fluorouracil (5-FU) is the inactivation of thymidylate synthase (TS) (EC 2.1.1.45) activity by the formation of a ternary complex consisting of covalently bound 5-fluorodeoxyuridine 5'-monophosphate (FdUMP), TS and 5,10-methylenetetrahydrofolate (CH2FH4). The gastrointestinal (GI) toxicity of 5-FU is also caused by its phosphorylation in the GI tract. Potassium oxonate (Oxo) competitively inhibits pyrimidine phosphoribosyltransferase (EC 2.4.2.10), which converts 5-FU to 5-fluorouridine 5'-monophosphate (FUMP) in vitro. In this study the benefits ofcombining Oxo and tegafur (FT), which is a masked compound of 5-FU, in reducing the GI toxicity of 5-FU and in protecting the activity of TS in the normal GI tissues were evaluated. Methods: We administered orally a preparation of 1 M FT and 0.4 M 5-chloro-2,4-dihydroxypyridine (CDHP) with or without 1 M Oxo (called S-1 and FT + CDHP, respectively) or vehicle only (control) to rats for ten consecutive days and compared the toxicity, the histopathological findings and the free TS activity in the GI tissues of the treated rats. Results: During the experimental periods, the signs of toxicity, such as a decrease in body weight, diarrhea and death, were only observed in the rats treated with FT + CDHP. The histopathological findings in the ileum and colon samples from rats treated consecutively with S-1 on day 1, day 4, day 7 and day 10 were less frequent and more mild than in the samples from rats treated with FT + CDHP. Furthermore, the free TS activities in the ileum samples of rats given S-1 and FT + CDHP were significantly decreased compared with the activity in samples from the control rats throughout the experimental periods. The free TS activities in GI tissues of rats treated with S-1 were higher than the TS activities in tissues from rats treated with FT + CDHP daily from day 4 to day 10, although activities in S-1-treatedrat were decreased to almost same low levels as in FT + CDHP-treated rats on day 1. Conclusions: Our results suggest that repeated simultaneous administration of Oxo and FT can effectively protect the activity of TS by decreasing FdUMP via FUMP from 5-FU in GI tissue, and may lead to a reduction inGI toxicity.

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Documento generato il 01/04/20 alle ore 10:50:19