5-Fluorouracil: mechanisms of action and clinical strategies

Key Points The fluoropyrimidine 5-fluorouracil (5-FU) is an antimetabolite drug that is widely used for the treatment of cancer, particularly for colorectal cancer. 5-FU exerts its anticancer effects through inhibition of thymidylate synthase (TS) and incorporation of its metabolites into RNA and DNA. Modulation strategies, such as co-treatment with leucovorin and methotrexate, have been developed to increase the anticancer activity of 5-FU. Molecular biomarkers that predict tumour sensitivity to 5-FU have been identified, including mRNA and protein expression levels of TS. DNA microarray analysis of 5-FU-responsive genes will greatly facilitate the identification of new biomarkers, novel therapeutic targets and the development of rational drug combinations. 5-Fluorouracil (5-FU) is widely used in the treatment of cancer. Over the past 20 years, increased understanding of the mechanism of action of 5-FU has led to the development of strategies that increase its anticancer activity. Despite these advances, drug resistance remains a significant limitation to the clinical use of 5-FU. Emerging technologies, such as DNA microarray profiling, have the potential to identify novel genes that are involved in mediating resistance to 5-FU. Such target genes might prove to be therapeutically valuable as new targets for chemotherapy, or as predictive biomarkers of response to 5-FU-based chemotherapy.