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

S-1 is a new oral formulation of 5-fluorouracil (5-FU) containing IM tegafu r and 0.4M 5-chloro-2,4-dihydroxypyridine (CDHP) and 1 M potassium oxonate (Oxo). It has been reported to have a high antitumor activity and low gastr ointestinal toxicity in rats bearing murine and human tumors. We further st udied 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 an d Oxo, an inhibitor of 5-FU phosphorylation. In a model of pentylenetetrazo le-induced convulsions in mice, intravenous injection of fluoroacetate (3 m g/kg), 2 fluoro-b-alanine (30 mg/kg) and 5-FU (over 300 mg/kg) significantl y augmented the occurrence of convulsion. However coadministration of an eq uivalent dose of CDHP with 5-FU almost completely suppressed the 5-FU-augme nted convulsions, suggesting that inhibition of 5-FU catabolism by CDHP may lead to a decreased risk of development of 5-FU neurotoxicity. Another adv antage of the use of S-1 was protection through Oxo against the development of 5-FU-induced mucositis, which occurs frequently in cancer patients. Whe n 6 mg/kg of S-1 was administered orally to beagle dogs for 5 days, the inc idence of stomatitis decreased markedly compared to that in dogs receiving the same dose of S-1 not containing Oxo, in which severe stomatitis was fre quently observed. One of the possible mechanisms of the decreased incidence of mucositis associated with oral S-1 administration is the decreased form ation of 5-fluoronucleotides from 5-FU in the mucosal tissues of the oral c avity. These results suggest that oral S-1 could be employed for the treatm ent of cancer patients with marked reduction in the incidence of toxicities including encephalopathy, stomatitis and diarrhea.