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.

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PubMedDate not supplied

5-Fluorouracil induces apoptotic cell death with G2 phase arrest in human breast cancer grafted in nude mice.

Treatment with 5-fluorouracil and its derivatives causes DNA double strand breaks in the S phase, and the subsequent cell death. A 5-Fluorouracil derivative (UFT), that is converted to 5-fluorouracil in vivo, was administered orally at a dose of 18 mg/kg/day to nude mice bearing human breast cancer for 28 consecutive days. The tumors on day 7, 14, 21, and 28 after treatment were examined histopathologically and by flow cytometric cell cycle analysis. UFT treatment achieved remarkable inhibition of tumor growth, and histological examination revealed significantly less mitotic figures and more apoptotic bodies throughout the treated tumors, compared to the controls. Flow cytometric study showed changes in the cell cycle outflow of treated tumor cells, involving reduced numbers of G1 phase cells and increased numbers of S and G2 phase cells, compared to the corresponding controls. The reduced growth of tumors induced by UFT is attributable to a rise in apoptotic cell death as well as a decline in producing daughter cells, i.e. mitotic activity, and 5-fluorouracil may act cytotoxically on cancer cells via apoptosis, followed by arrest at G2 phase.

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PubMedDate not supplied

Effect of combination therapy with UFT plus cisplatin (UFTP) on the survival of mice in the experimental model for wide-spread metastasis in the peritoneal cavity of gastrointestinal cancer using colon 26 PMF-15 cells.

The prognosis of unresectable advanced gastric cancer patients, especially with wide-spread metastasis in the peritoneal cavity, is very poor. In such cases, only a few treatment methods are available, and chemotherapy as a systemic therapy is often selected. We recently devised an experimental model for wide-spread metastasis in the peritoneal cavity of gastrointestinal cancer, by intraperitoneally implanting colon 26 murine carcinoma PMF-15 cells. When the control mice were autopsied, a number of tumor nodules were formed in their mesenterium, pancreas, liver, etc. and pools of ascites were also occasionally seen. Using this model, oral UFT (combining tegafur and uracil at a molar ratio of 1:4) plus cisplatin (UFTP regimen) prolonged the survival of mice and maintained these mice in relatively better condition than with continuous infusion of 5-fluorouracil plus cisplatin (FP regimen). Since UFT can be used orally, patients receiving UFTP therapy are not required to stay in a hospital for long periods, but rather, are intermittently hospitalized for short periods of time. Better QOL and prolonged survival highlight the potential clinical usefulness of the UFTP therapy.

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