Possible regulation of 5-fluorouracil-induced neuro- and oral toxicities by two biochemical modulators consisting of S-1, a new oral formulation of 5-fluorouracil

Anticancer Res. May-Jun 2001;21(3B):1705-12.


S-1 is a new oral formulation of 5-fluorouracil (5-FU) containing 1 M tegafur and 0.4 M 5-chloro-2,4-dihydroxypyridine (CDHP) and 1 M potassium oxonate (Oxo). It has been reported to have a high antitumor activity and low gastrointestinal toxicity in rats bearing murine and human tumors. We further studied the possible inhibition of the toxicities caused by the products of 5-FU metabolism with the use of CDHP, a new inhibitor of 5-FU degradation and Oxo, an inhibitor of 5-FU phosphorylation. In a model of pentylenetetrazole-induced convulsions in mice, intravenous injection of fluoroacetate (3 mg/kg), 2-fluoro-b-alanine (30 mg/kg) and 5-FU (over 300 mg/kg) significantly augmented the occurrence of convulsion. However coadministration of an equivalent dose of CDHP with 5-FU almost completely suppressed the 5-FU-augmented convulsions, suggesting that inhibition of 5-FU catabolism by CDHP may lead to a decreased risk of development of 5-FU neurotoxicity. Another advantage of the use of S-1 was protection through Oxo against the development of 5-FU-induced mucositis, which occurs frequently in cancer patients. When 6 mg/kg of S-1 was administered orally to beagle dogs for 5 days, the incidence of stomatitis decreased markedly compared to that in dogs receiving the same dose of S-1 not containing Oxo, in which severe stomatitis was frequently observed. One of the possible mechanisms of the decreased incidence of mucositis associated with oral S-1 administration is the decreased formation of 5-fluoronucleotides from 5-FU in the mucosal tissues of the oral cavity. These results suggest that oral S-1 could be employed for the treatment of cancer patients with marked reduction in the incidence of toxicities including encephalopathy, stomatitis and diarrhea.

MeSH terms

  • Animals
  • Anorexia / chemically induced
  • Antimetabolites, Antineoplastic / adverse effects*
  • Antimetabolites, Antineoplastic / pharmacology*
  • Carbon Radioisotopes / metabolism
  • Diarrhea / chemically induced
  • Dogs
  • Drug Combinations
  • Fluoroacetates / pharmacology
  • Fluorouracil / adverse effects*
  • Fluorouracil / analogs & derivatives
  • Fluorouracil / blood
  • Fluorouracil / pharmacology*
  • Injections, Intravenous
  • Male
  • Mice
  • Mice, Inbred ICR
  • Mouth Mucosa / drug effects
  • Mouth Mucosa / metabolism
  • Mouth Mucosa / pathology
  • Oxonic Acid / pharmacology*
  • Oxonic Acid / toxicity*
  • Pentylenetetrazole / pharmacology
  • Pyridines / pharmacology*
  • Pyridines / toxicity*
  • Tegafur / pharmacology*
  • Tegafur / toxicity*
  • Time Factors
  • Vomiting / chemically induced


  • Antimetabolites, Antineoplastic
  • Carbon Radioisotopes
  • Drug Combinations
  • Fluoroacetates
  • Pyridines
  • S 1 (combination)
  • Tegafur
  • Oxonic Acid
  • Fluorouracil
  • Pentylenetetrazole