Increased intestinal permeability correlates with gastrointestinal toxicity among formulations of the fluorouracil analogue tegafur in rats

Daisuke Korenaga, M. Honda, M. Yasuda, S. Inutsuka, T. Nozoe, H. Tashiro

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background: S-1 is a new antitumor agent which was developed based on biochemical modulation of fluorouracil. S-1 consists of tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1. S-1 has been reported to enhance therapeutic effects and to reduce the gastrointestinal toxicity as compared with 5-fluorouracil. In this study performed in rats, S-1 was used to assess the relationship between gastrointestinal mucosal toxicity and changes in intestinal barrier function. Methods: Fifteen rats were equally divided into three groups: group A (untreated controls), group B (FT and CDHP mixture), and group C (FT and CDHP in combination with Oxo). The animals in groups B and C received equitoxic doses of the drugs in their food for 14 consecutive days. The intestinal permeability was determined on the basis of the urinary recovery of orally administered lactulose and mannitol (L/M). Injury to the small intestines was evaluated by light microscopy. The cell surface expression of CD44 was evaluated immunohistochemically. Results: Recovery of L/M in urine (expressed as a fraction of the dose administered) was 0.15 ± (SE) 0.08, 0.23 ± 0.13, and 0.09 ± 0.04 in groups A, B, and C, respectively. The intestinal permeability in group B was significantly higher than that in group C (p<0.05). Treatment with FT and CDHP (groups B and C) induced injury to the small intestine and decreased expression of CD44 within the intestinal mucosa, but the extent of damage was reduced by coadministration of Oxo (group C). Conclusion: This experimental study suggested that the gastrointestinal toxicity resulting from administration of anticancer drugs is accompanied by an impaired gut barrier function measurable as an increase in intestinal permeability to L/M.

Original languageEnglish
Pages (from-to)351-356
Number of pages6
JournalEuropean Surgical Research
Volume34
Issue number5
DOIs
Publication statusPublished - Oct 17 2002

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Tegafur
Fluorouracil
Lactulose
Permeability
Mannitol
Small Intestine
Wounds and Injuries
Therapeutic Uses
Intestinal Mucosa
Pharmaceutical Preparations
Antineoplastic Agents
Microscopy
Urine
Light
Food
Control Groups
2,4-dihydroxypyridine

All Science Journal Classification (ASJC) codes

  • Surgery

Cite this

Increased intestinal permeability correlates with gastrointestinal toxicity among formulations of the fluorouracil analogue tegafur in rats. / Korenaga, Daisuke; Honda, M.; Yasuda, M.; Inutsuka, S.; Nozoe, T.; Tashiro, H.

In: European Surgical Research, Vol. 34, No. 5, 17.10.2002, p. 351-356.

Research output: Contribution to journalArticle

Korenaga, Daisuke ; Honda, M. ; Yasuda, M. ; Inutsuka, S. ; Nozoe, T. ; Tashiro, H. / Increased intestinal permeability correlates with gastrointestinal toxicity among formulations of the fluorouracil analogue tegafur in rats. In: European Surgical Research. 2002 ; Vol. 34, No. 5. pp. 351-356.
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abstract = "Background: S-1 is a new antitumor agent which was developed based on biochemical modulation of fluorouracil. S-1 consists of tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1. S-1 has been reported to enhance therapeutic effects and to reduce the gastrointestinal toxicity as compared with 5-fluorouracil. In this study performed in rats, S-1 was used to assess the relationship between gastrointestinal mucosal toxicity and changes in intestinal barrier function. Methods: Fifteen rats were equally divided into three groups: group A (untreated controls), group B (FT and CDHP mixture), and group C (FT and CDHP in combination with Oxo). The animals in groups B and C received equitoxic doses of the drugs in their food for 14 consecutive days. The intestinal permeability was determined on the basis of the urinary recovery of orally administered lactulose and mannitol (L/M). Injury to the small intestines was evaluated by light microscopy. The cell surface expression of CD44 was evaluated immunohistochemically. Results: Recovery of L/M in urine (expressed as a fraction of the dose administered) was 0.15 ± (SE) 0.08, 0.23 ± 0.13, and 0.09 ± 0.04 in groups A, B, and C, respectively. The intestinal permeability in group B was significantly higher than that in group C (p<0.05). Treatment with FT and CDHP (groups B and C) induced injury to the small intestine and decreased expression of CD44 within the intestinal mucosa, but the extent of damage was reduced by coadministration of Oxo (group C). Conclusion: This experimental study suggested that the gastrointestinal toxicity resulting from administration of anticancer drugs is accompanied by an impaired gut barrier function measurable as an increase in intestinal permeability to L/M.",
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AU - Honda, M.

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AU - Nozoe, T.

AU - Tashiro, H.

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