IN-VITRO TOXICITY OF N-3-METHYL-5'-DEOXY-5-FLUOROURIDINE, A NOVEL METABOLITE OF DOXIFLURIDINE - A BIOANALYTICAL INVESTIGATION

The cytotoxicity of N-3-methyl-5'-deoxy-5-fluorouridine (N-3-Me-5'-dFU R), a novel metabolite of the anticancer pro-drug 5'-deoxy-5-fluorouri dine (5'-dFUR), has been evaluated by in vitro experiments with cultur es of different cancer cell lines. The new metabolic product was found to be non-toxic in ail the cell growth experiments performed. The abs ence of cytotoxicity could be explained by the observation that the me tabolite was not recognized as a substrate by thymidine phosphorilase, the enzyme responsible for 5-fluorouracil (5-FU) release from doxiflu ridine, as ascertained by high-performance liquid chromatography/ultra violet (HPLC-UV) analysis of the incubation mixture. The biomethylatio n process leading to N-3-Me-5'-dFUR could be considered as a possible detoxification pathway, altering the drug bioavailability, in competit ion with 5'-dFUR cleavage to the active 5-FU. (C) 1998 Elsevier Scienc e B.V. All rights reserved.