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

• Published in: Anticancer research Vol. 21; no. 3B; p. 1705
• Main Authors: Kato, T, Shimamoto, Y, Uchida, J, Ohshimo, H, Abe, M, Shirasaka, T, Fukushima, M
• Format: Journal Article
• Language: English
• Published: Greece 01.05.2001
• Subjects: 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
• ISSN: 0250-7005

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.