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 E Talmadge, William H. Gmeiner

Research output: Contribution to journalArticle

19 Citations (Scopus)

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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Cytotoxicity
Fluorouracil
Toxicity
Fluorodeoxyuridylate
Drag
5-fluoro-2'-deoxyuridine
2'-deoxyuridylic acid
Thymidylate Synthase
Maximum Tolerated Dose
Prodrugs
Antineoplastic Agents
Cell culture
Culture Media
Colorectal Neoplasms
Nucleotides
Tumors
Cell Culture Techniques
Morbidity
Cells

ASJC Scopus subject areas

  • Biochemistry
  • Genetics

Cite this

Liu, J., Skradis, A., Kolar, C., Kolath, J., Anderson, J., Lawson, T., ... 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

Increased cytotoxicity and decreased in vivo toxicity of FdUMP[10] relative to 5-FU. / Liu, Jinqian; Skradis, Alan; Kolar, Carol; Kolath, Jeff; Anderson, James; Lawson, Terrence; Talmadge, James E; Gmeiner, William H.

In: Nucleosides and Nucleotides, Vol. 18, No. 8, 01.01.1999, p. 1789-1802.

Research output: Contribution to journalArticle

Liu, J, Skradis, A, Kolar, C, Kolath, J, Anderson, J, Lawson, T, Talmadge, JE & Gmeiner, WH 1999, 'Increased cytotoxicity and decreased in vivo toxicity of FdUMP[10] relative to 5-FU', Nucleosides and Nucleotides, vol. 18, no. 8, pp. 1789-1802. https://doi.org/10.1080/07328319908044843
Liu, Jinqian ; Skradis, Alan ; Kolar, Carol ; Kolath, Jeff ; Anderson, James ; Lawson, Terrence ; Talmadge, James E ; Gmeiner, William H. / Increased cytotoxicity and decreased in vivo toxicity of FdUMP[10] relative to 5-FU. In: Nucleosides and Nucleotides. 1999 ; Vol. 18, No. 8. pp. 1789-1802.
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