Standing the test of time: targeting thymidylate biosynthesis in cancer therapy

Peter M Wilson, Peter V Danenberg, Patrick G Johnston, Heinz-Josef Lenz, Robert D Ladner

Research output: Contribution to journalReview article

187 Citations (Scopus)

Abstract

Over the past 60 years, chemotherapeutic agents that target thymidylate biosynthesis and the enzyme thymidylate synthase (TS) have remained among the most-successful drugs used in the treatment of cancer. Fluoropyrimidines, such as 5-fluorouracil and capecitabine, and antifolates, such as methotrexate and pemetrexed, induce a state of thymidylate deficiency and imbalances in the nucleotide pool that impair DNA replication and repair. TS-targeted agents are used to treat numerous solid and haematological malignancies, either alone or as foundational therapeutics in combination treatment regimens. We overview the pivotal discoveries that led to the rational development of thymidylate biosynthesis as a chemotherapeutic target, and highlight the crucial contribution of these advances to driving and accelerating drug development in the earliest era of cancer chemotherapy. The function of TS as well as the mechanisms and consequences of inhibition of this enzyme by structurally diverse classes of drugs with distinct mechanisms of action are also discussed. In addition, breakthroughs relating to TS-targeted therapies that transformed the clinical landscape in some of the most-difficult-to-treat cancers, such as pancreatic, colorectal and non-small-cell lung cancer, are highlighted. Finally, new therapeutic agents and novel mechanism-based strategies that promise to further exploit the vulnerabilities and target resistance mechanisms within the thymidylate biosynthesis pathway are reviewed.

Original languageEnglish
Pages (from-to)282-98
Number of pages17
JournalNature reviews. Clinical oncology
Volume11
Issue number5
DOIs
Publication statusPublished - May 2014
Externally publishedYes

Keywords

  • Antimetabolites, Antineoplastic
  • Antineoplastic Combined Chemotherapy Protocols
  • DNA Repair
  • DNA Replication
  • DNA, Neoplasm
  • Drug Design
  • Drug Resistance, Neoplasm
  • Folic Acid Antagonists
  • Humans
  • Models, Biological
  • Neoplasm Proteins
  • Neoplasms
  • Prodrugs
  • Pyrimidines
  • Thymidine Monophosphate
  • Thymidylate Synthase
  • Journal Article
  • Review

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