title: Low uracil concentration in the liver might be responsible for the decreased antineoplastic activity of fluoropyrimidines in mice with CCl4-induced chronic liver dysfunction.
abstract: Some fluoropyrimidines are considered to be metabolized in liver microsomes. The present study was designed to assess the effect of chronic liver dysfunction on the antineoplastic activity of fluoropyrimidines. Chronic liver dysfunction was induced in BALB/c mice by 8 weeks of CCl4 injections. The 5-fluorouracil (5-FU)-sensitive MOPC-104E and 5-FU-resistant Meth-A cells were inoculated subcutaneously into the mice and then various fluoropyrimidines were administered intragastrically. The antitumor activity of the fluoropyrimidines decreased in mice with chronic liver dysfunction, although the concentration of 5-FU in the tumor of normal mice did not differ from that of mice with liver dysfunction. However, the concentration of uracil in the liver was decreased in mice with chronic liver dysfunction. On the other hand, the percent conversion of Tegafur [1-(2-tetrahydrofuryl)-5-FU] to 5-FU in the normal liver did not differ from that in the dysfunctional liver. These results suggest that low uracil concentrations in the liver may result from chronic liver dysfunction and lead to decreased antitumor efficacy of fluoropyrimidines.
authors.affiliation: First Department of Surgery, Kyoto University, Faculty of Medicine, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tsubono
authors.forename: Y
authors.initials: Y
authors.lastname: Nio
authors.forename: S
authors.initials: S
authors.lastname: Imai
authors.forename: T
authors.initials: T
authors.lastname: Shiraishi
authors.forename: H
authors.initials: H
authors.lastname: Morimoto
authors.forename: C C
authors.initials: CC
authors.lastname: Tseng
authors.forename: K
authors.initials: K
authors.lastname: Kawabata
authors.forename: M
authors.initials: M
authors.lastname: Fukumoto
authors.forename: T
authors.initials: T
authors.lastname: Tobe
mesh_terms: D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D004351:Drug Resistance; D005354:Fibrosarcoma / Q000188:drug therapy / Q000378:metabolism; D005472:Fluorouracil / Q000031:analogs & derivatives*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D010954:Plasmacytoma / Q000188:drug therapy / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014498:Uracil / Q000378:metabolism*
chemical_list: D014498:Uracil; D005472:Fluorouracil