title: Increased cytotoxicity and decreased in vivo toxicity of FdUMP[10] relative to 5-FU.
abstract: The efficacy of treatment with 5-Fluorouracil (5-FU) is limited, in part, by its inefficient conversion to 5-Fluoro-2'-deoxyuridine-5'-O-monophosphate (FdUMP). We present data indicating that FdUMP[10], designed as a pro-drug for intracellular release of FdUMP, is cytotoxic as a consequence of uptake of the multimeric form. FdUMP[10] is stable in cell culture medium, with more than one-half of the material persisting as multimers of at least six nucleotides after a 48 h incubation at 37 degrees C. FdUMP[10] is more than 400 times more cytotoxic than 5-FU towards human colorectal tumor cells (H630). FdUMP[10] also has decreased toxicity in vivo, with doses as high as 200 mg/kg/day (qdx3) administered to Balb/c mice without morbidity, compared to a maximum tolerated dose of 45 mg/kg/day for 5-FU using the same protocol. FdUMP[10] shows reduced sensitivity to OPRTase- and TK-mediated drug resistance, relative to 5-FU and FdU, respectively, and is much more cytotoxic than 5-FU towards cells that overexpress thymidylate synthase. Thus, FdUMP[10] is less susceptible to resistance mechanisms that limit the clinical utility of 5-FU. The increased cytotoxicity, decreased toxicity in vivo, and reduced sensitivity to drug resistance of FdUMP[10], relative to 5-FU, indicates multimeric FdUMP is potentially valuable as an anti-neoplastic agent, either as a single agent, or in combination with 5-FU.
authors.affiliation: Eppley Institute, University of Nebraska Medical Center, Omaha 68198-6805, USA.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: A
authors.initials: A
authors.lastname: Skradis
authors.forename: C
authors.initials: C
authors.lastname: Kolar
authors.forename: J
authors.initials: J
authors.lastname: Kolath
authors.forename: J
authors.initials: J
authors.lastname: Anderson
authors.forename: T
authors.initials: T
authors.lastname: Lawson
authors.forename: J
authors.initials: J
authors.lastname: Talmadge
authors.forename: W H
authors.initials: WH
authors.lastname: Gmeiner
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D001711:Biotransformation; D001835:Body Weight / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D005468:Fluorodeoxyuridylate / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D005472:Fluorouracil / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D006207:Half-Life; D006801:Humans; D007928:Lethal Dose 50; D051379:Mice; D008807:Mice, Inbred BALB C; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009962:Orotate Phosphoribosyltransferase / Q000378:metabolism; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D013937:Thymidine Kinase / Q000378:metabolism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D011355:Prodrugs; D005468:Fluorodeoxyuridylate; D013940:Thymidylate Synthase; D009962:Orotate Phosphoribosyltransferase; D013937:Thymidine Kinase; D005472:Fluorouracil