title: Stimulation of 5-fluorouracil metabolic activation by interferon-alpha in human colon carcinoma cells.
abstract: Interferon-alpha (IFN alpha) increases the cytotoxicity of 5-fluorouracil (FUra) in vitro, and the combination has clinical efficacy against advanced colorectal cancer. IFN alpha treatment of HT-29 colon carcinoma cells induced a greater than two-fold increase in the intracellular levels of the active metabolite of FUra, FdUMP. Using cell extracts from HT-29 cells and FUra as substrate, IFN alpha produced a 1.9- and 8.7-fold increase, respectively, in the activities of uridine phosphorylase and pyrimidine nucleoside phosphorylase (PyNP). Furthermore, the effect was selective for the conversion of FUra to FdUMP, as IFN alpha did not increase the cellular levels of FUTP, nor did it change the extent of incorporation of FUra into RNA (or DNA). IFN alpha also had no effect on thymidine kinase activity, the second step in the activation of FUra. Hence the effect of IFN alpha on PyNP activity is likely a critical biochemical event that modulates the cytotoxicity of FUra.
authors.affiliation: Department of Oncology, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: E L
authors.initials: EL
authors.lastname: Schwartz
authors.forename: M
authors.initials: M
authors.lastname: Hoffman
authors.forename: C J
authors.initials: CJ
authors.lastname: O'Connor
authors.forename: S
authors.initials: S
authors.lastname: Wadler
mesh_terms: D000241:Adenosine / Q000378:metabolism; D001711:Biotransformation; D002460:Cell Line; D003110:Colonic Neoplasms; D004273:DNA, Neoplasm / Q000096:biosynthesis; D005472:Fluorouracil / Q000378:metabolism*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D007700:Kinetics; D012334:RNA, Neoplasm / Q000096:biosynthesis; D011865:Radioisotope Dilution Technique; D011994:Recombinant Proteins; D013936:Thymidine / Q000378:metabolism; D014316:Tritium
chemical_list: D004273:DNA, Neoplasm; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012334:RNA, Neoplasm; D011994:Recombinant Proteins; D014316:Tritium; D000241:Adenosine; D005472:Fluorouracil; D013936:Thymidine