5-Fluorouracil for colorectal cancer: mechanism of action and metabolism

Abstract

In the palliative and adjuvant treatment of colorectal cancer (CRC), 5-fluorouracil (5-FU) is crucial part of systemic chemotherapy. In order to improve the anti-tumor efficacy of 5-FU and prevent clinical resistance, a number of modulation techniques, including the use of 5-FU pro-drugs and 5-FU-based combination regimens, have been created and tested over the past 60 years. Despite the positive developments in CRC treatment to date, low response rates in patients and frequent development of chemoresistance limit the benefits of 5-FU-based therapy for patients. The individual’s distinct genetic and epigenetic makeup may be the root cause of inter-individual variations in the response to therapy in CRC patients. A correct understanding of the factors contributing to the low or absent sensitivity of tumor tissue to 5-FU-based therapy is a crucial component in the current trend of personalized medicine. Future patient outcomes will probably be improved by the discovery and confirmation of predictive biomarkers for current 5-FU-based and new targeted medicines for CRC treatment. Here, we present a thorough overview of CRC therapeutic options and the molecular mechanisms of 5-FU action, including both catabolic and anabolic effects. The main focus of this review is on the molecular processes that underlie chemoresistance in CRC patients. We additionally focus on several 5-FU pro-drugs developed to improve levels of circulating 5-FU while lowering toxicity.

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