Background: Fluoropyrimidines (FPs) have been used for a long time as first-line treatment
for colorectal cancer and continue to represent the backbone of combination chemotherapy in
both the adjuvant and metastatic disease settings. In a consistent percentage of patients (10-40%) FPs
induce severe to life-threatening toxicity. On this basis, markers of tolerance to treatment need to be
found. Dihydropyrimidine dehydrogenase (DPYD) pharmacogenetic screening is a useful tool to
identify individuals at high risk of FPs severe toxicity. However, constitutional DPYD mutations only
partially explain polymorphic DPD activity and toxic response. Recent advances in research have
suggested that epigenetic mechanisms may provide a new source of explanations in the context of drugassociated
Objective and Methods: A systematic literature search of MEDLINE and EMBASE databases was performed
in order to review the current state of knowledge about epigenetic aspects related to fluoropyrimidine-
Results: Various genes and pathways involved in FPs metabolism and mechanism of action have been
shown to be regulated by promoter methylation and specific miRNA expression at the transcriptional
level, responsible for an intrinsic or acquired chemoresistance. Also, preclinical evidences are accumulating
that epigenetic drugs may increase cell chemosensitivity.
Conclusion: Associations between epigenetic patterns and effects of FPs have been outlined and some
critical issues on the translation to clinical practice discussed.