Increased cytotoxicity and decreased in vivo toxicity of FdUMP[10] relative to 5-FU

Jinqian Liu, Alan Skradis, Carol Kolar, Jeff Kolath, James Anderson, Terrence Lawson, James Talmadge, William H. Gmeiner

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19 Scopus citations

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 °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 drag 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 drag resistance of FdUMP[10], relative to 5- FU, indicates multimeric FdUMP is potentially valuable as an antineoplastic agent, either as a single agent, or in combination with 5-FU.

Original languageEnglish (US)
Pages (from-to)1789-1802
Number of pages14
JournalNucleosides and Nucleotides
Volume18
Issue number8
DOIs
StatePublished - Jan 1 1999

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ASJC Scopus subject areas

  • Biochemistry
  • Genetics

Cite this

Liu, J., Skradis, A., Kolar, C., Kolath, J., Anderson, J., Lawson, T., Talmadge, J., & Gmeiner, W. H. (1999). Increased cytotoxicity and decreased in vivo toxicity of FdUMP[10] relative to 5-FU. Nucleosides and Nucleotides, 18(8), 1789-1802. https://doi.org/10.1080/07328319908044843