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Desensitization and sensitization of cells to fluoropyrimidines with different antisenses directed against

J Ju1, S E Kane, H J Lenz

  • 1USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles 90033, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|September 25, 1998
PubMed

Insights

Antisense oligodeoxyribonucleotides (ODNs) targeting thymidylate synthase (TS) can decrease TS expression in cancer cells. This approach enhances sensitivity to fluoropyrimidine chemotherapy, offering a potential strategy for improved cancer treatment.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Antisense Technology

Background:

  • Fluoropyrimidines are a class of chemotherapy drugs whose efficacy is largely dependent on inhibiting thymidylate synthase (TS).
  • Understanding mechanisms to modulate TS expression is crucial for enhancing the effectiveness of fluoropyrimidine-based cancer therapies.

Purpose of the Study:

  • To investigate the potential of using antisense oligodeoxyribonucleotides (ODNs) to decrease thymidylate synthase (TS) expression.
  • To determine if reducing TS expression can increase the chemosensitivity of human cancer cells to fluoropyrimidines.

Main Methods:

  • Antisense ODNs targeting the AUG translational initiation site of TS mRNA were designed and tested in vitro.
  • Human colon cancer HT-29 cells and human nasopharyngeal cancer KB31 cells were treated with antisense ODNs or transfected with a plasmid expressing antisense TS RNA.
  • TS catalytic activity, protein levels, and sensitivity to 5-fluoro-2'-deoxyuridine (FdUrd) were assessed.

Main Results:

  • Antisense ODNs inhibited TS mRNA translation in a cell-free system.
  • Short-term treatment of HT-29 cells decreased TS activity, but long-term treatment paradoxically increased TS levels and reduced FdUrd sensitivity.
  • Transfection of KB31 cells with a TS antisense construct significantly decreased TS expression and activity, leading to an 8-fold enhancement in FdUrd sensitivity.
  • No changes in sensitivity to cisplatin or Adriamycin were observed.

Conclusions:

  • Antisense RNA targeting thymidylate synthase (TS) can effectively down-regulate TS expression in human cancer cells.
  • Reducing TS expression via antisense technology can significantly enhance the sensitivity of cancer cells to fluoropyrimidine drugs.
  • This strategy holds promise for improving the efficacy of fluoropyrimidine-based cancer chemotherapy.

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