Thymidylate synthase inhibitors as anticancer agents: From bench to bedside

Edward Chu, Marc A. Callender, Michael P. Farrell, John C. Schmitz

Research output: Contribution to journalArticlepeer-review

167 Scopus citations


Thymidylate synthase (TS) is a folate-dependent enzyme that catalyzes the reductive methylation of 2′-deoxyuridine-5′-monophosphate to 2′-deoxythymidine-5′-monophosphate. This pathway provides the sole intracellular de novo source of 2′-deoxythymidine-5′-triphosphate; therefore, TS represents a critical target in cancer chemotherapy. 5-Fluorouracil (5-FU) was synthesized in 1957 and represents the first class of antineoplastic agents to be developed as inhibitors of TS. While 5-FU has been widely used to treat various human malignancies, its overall clinical efficacy is limited. Therefore, significant efforts have focused on the design of novel, more potent inhibitor compounds of TS. These agents fall into two main categories: folate analogs and nucleotide analogs. Five antifolate analogs are currently being evaluated in the clinic: raltitrexed, pemetrexed, nolatrexed, ZD9331, and GS7904L. Our laboratory has identified a novel mechanism of resistance that develops to TS inhibitor compounds, namely drug-mediated acute induction of new TS synthesis; this mechanism is directly controlled at the translational level. The ability of cancer cells to acutely induce the expression of TS may represent a novel mechanism for the development of cellular drug resistance. The future success of TS inhibitor compounds in the clinic may depend on novel strategies to selectively inhibit TS and on novel combination therapies to overcome cellular drug resistance.

Original languageEnglish (US)
Pages (from-to)S80-S89
JournalCancer Chemotherapy and Pharmacology, Supplement
Issue number1
StatePublished - 2003
Externally publishedYes


  • 5-Fluorouracil
  • Antifolates
  • Cancer chemotherapy
  • Drug resistance
  • Thymidylate synthase

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Cancer Research


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