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Related Experiment Videos

Diverse gene expression pattern during 5-fluorouridine-induced apoptosis.

Thomas D Schmittgen1, Kari A Gissel, Brian A Zakrajsek

  • 1College of Pharmacy, Ohio State University, L.M. Parks Hall, Columbus, OH 43210, USA. schmittgen.2@osu.edu

International Journal of Oncology
|July 13, 2005
PubMed
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This study shows that 5-fluorouridine induces apoptosis in colorectal cancer cells by altering gene expression. Uridine addition prevents this cell death, highlighting specific molecular pathways involved in fluoropyrimidine cytotoxicity.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Pharmacology

Background:

  • Fluoropyrimidines, like 5-fluorouridine, are widely used in cancer chemotherapy.
  • Understanding the precise mechanisms of their cytotoxicity, including gene expression changes during apoptosis, is crucial for optimizing treatment.
  • HCT-116 colorectal carcinoma cells provide a relevant model for studying these effects.

Purpose of the Study:

  • To establish conditions for inducing apoptosis using 5-fluorouridine in HCT-116 cells.
  • To investigate the global gene expression changes occurring during 5-fluorouridine-induced apoptosis.
  • To elucidate the role of uridine and thymidine in modulating 5-fluorouridine's effects.

Main Methods:

  • HCT-116 cells were treated with 5-fluorouridine under various conditions (alone, with uridine, with thymidine).

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  • Apoptosis and cell viability were assessed over time.
  • cDNA microarray analysis was employed to profile the expression of 1,200 genes.
  • Main Results:

    • 5-fluorouridine induced apoptosis in a time-dependent manner, significantly reducing cell viability when uridine was absent (p < 0.001).
    • Uridine co-administration abrogated the apoptotic effect of 5-fluorouridine.
    • Microarray analysis revealed significant upregulation of 33 genes (including growth factors, cytokines, and chemokines like MIC-1) and downregulation of 124 genes.

    Conclusions:

    • 5-fluorouridine triggers a complex pattern of gene expression changes during apoptosis in HCT-116 cells.
    • The cytotoxicity of fluoropyrimidines involves mechanisms beyond simple RNA synthesis inhibition.
    • Uridine plays a critical role in counteracting 5-fluorouridine-induced apoptosis, suggesting potential therapeutic strategies.