Thymidylate synthase and drug resistance

G. J. Peters, C. L. van der Wilt, B. van Triest, G. Codacci-Pisanelli, P. G. Johnston, C. J. van Groeningen, H. M. Pinedo

Research output: Contribution to journalArticle

Abstract

Thymidylate synthase is an important target for both fluorinated pyrimidines and for new folate analogues. Resistance to 5-fluorouracil (5FU) can be related to insufficient inhibition of thymidylate synthase. The 5FUnucleotide FdUMP induces inhibition of thymidylate synthase which is enhanced and retained for longer in the presence of increased folate pools, for which leucovorin is a precursor. In a murine model system, 5FU treatment caused a 4-fold induction of thymidylate synthase levels which may have contributed to resistance. Addition of leucovorin to this treatment prevented this induction and increased the antitumour effect 2-3-fold. In the clinical setting, 5FU administration to patients resulted in approximately 50% inhibition of TS after 48 h. The combination with leucovorin resulted in a more pronounced inhibition after 48 h (approximately 70%). A significant relationship was observed with outcome of treatment; when thymidylate synthase levels were high and inhibition was low, no response was observed. A separate study showed that low thymidylate synthase levels appeared to be an independent prognostic factor for adjuvant therapy.

Original languageEnglish (US)
Pages (from-to)1299-1305
Number of pages7
JournalEuropean Journal of Cancer
Volume31
Issue number7-8
DOIs
StatePublished - 1995
Externally publishedYes

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Keywords

  • 5-fluorouracil
  • antifolates
  • folates
  • leucovorin
  • resistance
  • thymidylate synthase

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Hematology

Cite this

Peters, G. J., van der Wilt, C. L., van Triest, B., Codacci-Pisanelli, G., Johnston, P. G., van Groeningen, C. J., & Pinedo, H. M. (1995). Thymidylate synthase and drug resistance. European Journal of Cancer, 31(7-8), 1299-1305. https://doi.org/10.1016/0959-8049(95)00172-F