Inhibition by oxonic acid of gastrointestinal toxicity of 5-fluorouracil without loss of its antitumor activity in rats.

Abstract

The possibility of decreasing the gastrointestinal (GI) toxic effects of 5-fluorouracil (5-FU) on the digestive tract such as its injury of cells and induction of diarrhea, without reducing its antitumor activity, was investigated in rats. Oxonic acid was found to inhibit the phosphorylation of 5-FU to 5-fluorouridine-5'-monophosphate catalyzed by pyrimidine phosphoribosyl-transferase in a different manner from allopurinol in cell-free extracts and intact cells in vitro. On p.o. administration of 5-FU (2 mg/kg) and a potent inhibitor of 5-FU degradation to Yoshida sarcoma-bearing rats, oxonic acid (10 mg/kg) was found to inhibit the formation of 5-fluorouridine-5'-monophosphate from 5-FU and its subsequent incorporation into the RNA fractions of small and large intestine but not of tumor and bone marrow tissues. This selective inhibition of 5-FU phosphorylation in the GI tract was due to the much higher concentrations of oxonic acid in GI tissues than in other tissues and the blood. On p.o. administration with the 5-FU derivative, UFT, which is a combined form of 1 M tegafur and 4 M uracil and usually administered p.o. to cancer patients in Japan, oxonic acid (10-50 mg/kg) markedly reduced injury of GI tissues and/or severe diarrhea without influencing the antitumor effect of UFT. These findings suggest that coadministration of oxonic acid suppresses the GI toxicity of 5-FU and its derivatives without affecting their antitumor activity and thus prolongs the life span of cancer-bearing rats.

• Authors: T Shirasaka, Y Shimamoto, M Fukushima
• Journal: Cancer research (Cancer Res) Vol. 53 Issue 17 Pg. 4004-9 (Sep 01 1993) ISSN: 0008-5472 [Print] United States
• PMID: 7689420 (Publication Type: Journal Article)

Chemical References

• Uracil Nucleotides
• Oxonic Acid
• RNA
• 5-fluorouridine 5'-phosphate
• Fluorouracil

Topics

• Administration, Oral
• Animals
• Digestive System (drug effects, metabolism)
• Fluorouracil (administration & dosage, adverse effects, antagonists & inhibitors, metabolism)
• Infusions, Intravenous
• Liver (metabolism)
• Male
• Oxonic Acid (administration & dosage, metabolism, pharmacology)
• Phosphorylation (drug effects)
• RNA (metabolism)
• Rats
• Sarcoma, Yoshida (drug therapy, metabolism)
• Uracil Nucleotides (metabolism)