Transcription and activity of 5-fluorouracil converting enzymes in fluoropyrimidine resistance in colon cancer in vitro

Biochemical Pharmacology
R M MaderG G Steger

Abstract

Cellular resistance to 5-fluorouracil (5-FU) is not completely understood. Since 5-FU shares the pyrimidine pathway with the physiological pyrimidines, we investigated the relationship between fluoropyrimidine metabolism, nucleic acid uptake and cytotoxicity of 5-FU in eight colon tumour cell lines including 5-FU-resistant subclones. The cytotoxicity of 5-FU was increased up to 423-fold when the anabolites 5-fluorouridine (FUrd), 5-fluorodeoxyuridine (FdUrd), and 5-fluorodeoxyuridine monophosphate (FdUMP) were compared with the parent drug in vitro. The enzymes uridine phosphorylase and thymidine phosphorylase were predictive for the cytotoxicity of 5-FU in 5/7 cell lines. Inhibition of uridine phosphorylase and thymidine phosphorylase by antisense strategies effectively antagonised 5-FU, abolishing 84% and 79% of its toxicity. The importance of thymidine phosphorylase was supported by a highly restricted enzyme activity in 5-FU-resistant cells. In 5-FU naive cells, a stimulating effect of 5-FU on thymidylate synthase mRNA and ribonucleotide reductase mRNA expression was observed. In these cells, antisense oligonucleotides to ribonucleotide reductase significantly reduced cell growth. Downregulation of ribonucleotide reductase ...Continue Reading

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Citations

Dec 23, 2003·Applied Radiation and Isotopes : Including Data, Instrumentation and Methods for Use in Agriculture, Industry and Medicine·Tae Hyun ChoiSang Moo Lim
Nov 11, 1998·General Pharmacology·R M MaderG G Steger
Jul 19, 2003·Human Gene Therapy·Victor A LewisPaul J Orchard
Nov 24, 1998·Antisense & Nucleic Acid Drug Development·J C SchmitzE Chu
Sep 14, 2004·International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society·J Q CuiJ Q Li
Feb 16, 2008·PPAR Research·Daniel C Berry, Noa Noy
Mar 29, 2007·PPAR Research·Rinke StienstraSander Kersten
Sep 8, 2004·International Journal of Cancer. Journal International Du Cancer·Wolfgang M SchmidtRobert M Mader
Aug 28, 2007·International Journal of Cancer. Journal International Du Cancer·Xanthi N StahteaNikos K Karamanos
Nov 2, 2018·Analytical Chemistry·Gerald StübigerRobert M Mader
Jan 17, 2020·Journal of Chemical Information and Modeling·Maciej Pyrka, Maciej Maciejczyk

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