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 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.
Kato
T
T
The Second Cancer Laboratory, Taiho Pharmaceutical Co. Ltd., Hanno-City, Saitama, Japan.
Shimamoto
Y
Y
Uchida
J
J
Ohshimo
H
H
Abe
M
M
Shirasaka
T
T
Fukushima
M
M
D000818:Animals; D000855:Anorexia / Q000139:chemically induced; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000494:pharmacology*; D002250:Carbon Radioisotopes / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced; D004285:Dogs; D004338:Drug Combinations; D005463:Fluoroacetates / Q000494:pharmacology; D005472:Fluorouracil / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009061:Mouth Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010094:Oxonic Acid / Q000494:pharmacology* / Q000633:toxicity*; D010433:Pentylenetetrazole / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology* / Q000633:toxicity*; D005641:Tegafur / Q000494:pharmacology* / Q000633:toxicity*; D013997:Time Factors; D014839:Vomiting / Q000139:chemically induced
D000964:Antimetabolites, Antineoplastic; D002250:Carbon Radioisotopes; D004338:Drug Combinations; D005463:Fluoroacetates; D011725:Pyridines; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D005472:Fluorouracil; D010433:Pentylenetetrazole