Methyl-Group Metabolism and the Response of Colorectal Cancer to 5-Fluorouracil

Abstract

The major mechanism of action of 5-fluorouracil (5FU)-based therapies is thought to be inhibition of thymidylate synthase (TS). This enzyme catalyzes synthesis of the thymidine nucleotide precursor using a methyl group provided by a folate cofactor. In addition to TS activity levels, various elements of methyl-group metabolism could also be predictive for the response of colorectal cancer (CRC) to 5FU. These include the activity of enzymes involved in folate metabolism, the concentrations of intracellular folate intermediates, and surrogate markers of aberrant methyl-group metabolism, such as DNA methylation and microsatellite instability. The factors of age, gender, common genetic variants, and diet have been shown to influence both systemic and tumor methyl-group metabolism. This has important implications for the prediction of toxicity and response to 5FU, respectively. Identification of predictive factors within the methyl-group metabolism pathway should assist in targeting 5FU treatment to the most responsive CRC patient groups. This is particularly important for early-stage disease where conclusive demonstration of a survival benefit from 5FU in the overall CRC group has thus far proven difficult.