Undetected toxicity risk in pharmacogenetic testing for dihydropyrimidine dehydrogenase

Felicia Stefania Falvella, Marta Caporale, Stefania Cheli, Antonia Martinetti, Rosa Berenato, Claudia Maggi, Monica Niger, Francesca Ricchini, Ilaria Bossi, Maria Di Bartolomeo, Elisa Sottotetti, Francesca Futura Bernardi, Filippo de Braud, Emilio Clementi, Filippo Pietrantonio

Research output: Contribution to journalArticlepeer-review

Abstract

Fluoropyrimidines, the mainstay agents for the treatment of colorectal cancer, alone or as a part of combination therapies, cause severe adverse reactions in about 10%–30% of patients. Dihydropyrimidine dehydrogenase (DPD), a key enzyme in the catabolism of 5-fluorouracil, has been intensively investigated in relation to fluoropyrimidine toxicity, and several DPD gene (DPYD) polymorphisms are associated with decreased enzyme activity and increased risk of fluoropyrimidine-related toxicity. In patients carrying non-functional DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T), fluoropyrimidines should be avoided or reduced according to the patients’ homozygous or heterozygous status, respectively. For other common DPYD variants (c.496A>G, c.1129-5923C>G, c.1896T>C), conflicting data are reported and their use in clinical practice still needs to be validated. The high frequency of DPYD polymorphism and the lack of large prospective trials may explain differences in studies’ results. The epigenetic regulation of DPD expression has been recently investigated to explain the variable activity of the enzyme. DPYD promoter methylation and its regulation by microRNAs may affect the toxicity risk of fluoropyrimidines. The studies we reviewed indicate that pharmacogenetic testing is promising to direct personalised dosing of fluoropyrimidines, although further investigations are needed to establish the role of DPD in severe toxicity in patients treated for colorectal cancer.

Original languageEnglish
Pages (from-to)8884-8895
Number of pages12
JournalInternational Journal of Molecular Sciences
Volume16
Issue number4
DOIs
Publication statusPublished - Apr 21 2015

Keywords

  • Dihydropyrimidine dehydrogenase
  • Fluoropyrimidines
  • Pharmacogenetics
  • Single nucleotide polymorphisms
  • Toxicity

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Spectroscopy
  • Inorganic Chemistry
  • Catalysis
  • Molecular Biology
  • Computer Science Applications

Fingerprint Dive into the research topics of 'Undetected toxicity risk in pharmacogenetic testing for dihydropyrimidine dehydrogenase'. Together they form a unique fingerprint.

Cite this