DNA mismatch repair (MMR)-dependent 5-fluorouracil cytotoxicity and the potential for new therapeutic targets

Long Shan Li, Julio C. Morales, Martina Veigl, David Sedwick, Sheldon Greer, Mark Meyers, Mark Wagner, Richard Fishel, David A. Boothman

Research output: Contribution to journalReview article

45 Scopus citations

Abstract

The metabolism and efficacy of 5-fluorouracil (FUra) and other fluorinated pyrimidine (FP) derivatives have been intensively investigated for over fifty years. FUra and its antimetabolites can be incorporated at RNA- and DNA-levels, with RNA level incorporation provoking toxic responses in human normal tissue, and DNA-level antimetabolite formation and incorporation believed primarily responsible for tumour-selective responses. Attempts to direct FUra into DNA-level antimetabolites, based on mechanism-of-action studies, have led to gradual improvements in tumour therapy. These include the use of leukovorin to stabilize the inhibitory thymidylate synthase-5-fluoro-2′-deoxyuridine 5′ monophoshate (FdUMP)-5,10-methylene tetrahydrofolate (5,10-CH 2FH 4) trimeric complex. FUra incorporated into DNA also contributes to antitumour activity in preclinical and clinical studies. This review examines our current state of knowledge regarding the mechanistic aspects of FUra:Gua lesion detection by DNA mismatch repair (MMR) machinery that ultimately results in lethality. MMR-dependent direct cell death signalling or futile cycle responses will be discussed. As 10-30% of sporadic colon and endometrial tumours display MMR defects as a result of human MutL homologue-1 (hMLH1) promoter hypermethylation, we discuss the use and manipulation of the hypomethylating agent, 5-fluorodeoxycytidine (FdCyd), and our ability to manipulate its metabolism using the cytidine or deoxycytidylate (dCMP) deaminase inhibitors, tetrahydrouridine or deoxytetrahydrouridine, respectively, as a method for re-expression of hMLH1 and re-sensitization of tumours to FP therapy.

Original languageEnglish (US)
Pages (from-to)679-692
Number of pages14
JournalBritish Journal of Pharmacology
Volume158
Issue number3
DOIs
StatePublished - Oct 1 2009

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Keywords

  • 5-fluorouracil
  • DNA mismatch repair
  • HMLH1
  • Hypermethylation
  • MMR/c-Abl/p73α/GADD45α signalling
  • Thymidylate synthase

ASJC Scopus subject areas

  • Pharmacology

Cite this

Li, L. S., Morales, J. C., Veigl, M., Sedwick, D., Greer, S., Meyers, M., Wagner, M., Fishel, R., & Boothman, D. A. (2009). DNA mismatch repair (MMR)-dependent 5-fluorouracil cytotoxicity and the potential for new therapeutic targets. British Journal of Pharmacology, 158(3), 679-692. https://doi.org/10.1111/j.1476-5381.2009.00423.x