Drug interaction of antitumor drugs. III. Antitumor activity of tegafur in lipopolysaccharide-treated mice.
The effect of lipopolysaccharide (obtained from Escherichia coli, LPS) on the antitumor activity, acute toxicity and metabolism of tegafur was investigated in mice in comparison with 5-fluorouracil (5-FU). It was found that the intravenous administration of LPS (1.25 or 2.5 mg/kg) 24 hr prior to tegafur decreased the antitumor activity of tegafur against the solid form of Sarcoma 180. On the acute toxicity of tegafur or 5-FU, the lethality of the former was decreased and that of the latter was enhanced by the pretreatment with LPS 24 hr before. In LPS-treated mice, after the administration of tegafur, the level of tegafur in plasma was higher and the elevated level maintained longer than in untreated mice; and a small amount of 5-FU was released. A high level of 5-FU in plasma after the administration of 5-FU was also observed in LPS-treated mice. In the liver and kidneys of LPS-treated mice, the level of 5-FU after the administration of tegafur or 5-FU was higher, and its conversion of 5-FU to fluorouridine (FUR) was lower than that of control mice. On the other hand, LPS inhibited significantly the hepatic drug-metabolizing enzymes 24 hr after. It can, therefore, be presumed that the antitumor activity of tegafur was affected with LPS as a result of inhibition of conversion from tegafur to 5-FU or from 5-FU to FUR mainly according to depression in the hepatic drug-metabolism.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004347:Drug Interactions; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000633:toxicity; D007668:Kidney / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D006899:Mixed Function Oxygenases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D005641:Tegafur / Q000494:pharmacology*; D013997:Time Factors
D000970:Antineoplastic Agents; D008070:Lipopolysaccharides; D011506:Proteins; D005641:Tegafur; D006899:Mixed Function Oxygenases; D005472:Fluorouracil