Thymidylate Synthase Gene in Pharmacogenetics

Thymidylate synthase (TS) is the target for widely used anticancer agent 5-fluorouracil (5-FU) and a number of other TS inhibitors are now either in clinical use or under development. The TS gene has a variable number of tandem repeat (VNTR) sequence, mainly 2 repeats (2R) and 3 repeats (3R), which are promising candidates for prediction of the effectiveness and adverse drug reactions of TS inhibitors. It has been demonstrated both in vitro and in vivo that the 3R allele is associated with higher levels of expression of TS mRNA or TS protein as compared to the 2R allele. This association provides a plausible explanation for the clinical observations that homozygous 3R / 3R patients have a lower probability of response and less frequent adverse drug effects of 5-FU-based chemotherapy than those homozygous for 2R / 2R or heterozygous for 2R / 3R. However, some studies found neither an association between TS VNTR genotype and TS expression nor any relationship between the genotype and clinical outcome of 5-FU-based chemotherapy. Recent studies suggested that other polymorphisms, gene alterations of TS and cancer phenotypes relevant to TS VNTR polymorphism may be involved in the outcome of 5-FU-based chemotherapy. These variables include loss of heterozygosity at the TS locus, novel single nucleotide polymorphism of TS, TS 1494del6 polymorphism and methylenetetrahydrofolate reductase polymorphism. Future clinical trials should collect information regarding these genetic variables to evaluate their predictive value and realize tailored chemotherapy in 5-FU-based chemotherapy.