Role of administration route in the therapeutic efficacy of doxifluridine
Trave, F.; Canobbio, L.; Au, J.L.; Rustum, Y.M.
Journal of the National Cancer Institute 78(3): 527-532
1987
ISSN/ISBN: 0027-8874 PMID: 2950266 Document Number: 290073
Efect of drug administration route on the therapeutic efficacy of the 5-fluorouracil (FUra) analogue doxifluridine [(5'-dFUrd); 5'-deoxy-5-fluorouridine] was investigated in Fischer CDF rats bearing a chemically induced transplantable colon carcinoma sensitive to fluoropyrimidines. The antitumor activities of 5'-dFUrd and of its parent drug FUra were evaluated after 7 days of continuous administration (by i.v. infusion, i.v. push, or po route) of doses ranging from 125 to 750 mg 5'-dFUrd/kg/day and from 12.5 to 55 mg FUra/kg/day. At the maximally tolerated dose, 5'-dFUrd (500 mg/kg/day) and FUra (25-35 mg/kd/day) were equally effective in producing cures when treatments were performed by either continuous i.v. infusion or i.v. push. 5'-dFUrd was more effective than FUra when these agents were administered orally (82% cures for 5'-dFUrd vs. 30% cures for FUra). Concentrations of 5'-dFUrd and its metabolite FUra in the blood and urine of normal and tumor-bearing rats were determined by high-performance liquid chromatography following administration of 500 mg 5'-dFUrd/kg. Pharmacokinetic studies indicated that at comparable antitumor activity, systemic exposures to FUra derived from 500 mg 5'-dFUrd/kg administered by i.v. push, orally, or continuous i.v. infusion were 3.5 .+-. 1.0, 3.2 .+-. 1.1, and 1.5 .+-. 0.3 mM .cntdot. min, respectively. Antitumor activity and pharmacokinetic results obtained in this model system indicated that 1) 5'-dFUrd is an active agent that can produce cures regardless of the route of administration employed and 2) among the three methods of drug administration tested, comparable tumor-free survival can be achieved by continuous i.v. infusion of 5'-dFUrd with the concomitant lowest systemic exposure to the cytotoxic metabolite FUra.