Thymidylate synthase pharmacogenetics in colorectal cancer.

Thymidylate synthase (TS) is an important target for chemotherapy drugs, such as 5-fluorouracil (5-FU), 5-fluorodeoxyuridine (FUDR), oral 5-FU prodrugs (e.g., uracil/tegafur [UFT], S-1, and capecitabine), and other novel folate-based drugs (e.g., raltitrexed, pemetrexed, and nolatrexed). Overexpression of TS is linked to resistance to TS-targeted chemotherapy drugs. Polymorphic tandem repeats located in the TS enhancer region (TSER) have been shown to influence TS expression. Three copies (TSER3) of the tandem repeat give a 2.6-fold greater in vitro TS expression than 2 copies (TSER2). A stepwise increase in expression and enzyme activity has been observed with increasing copies of the TSER. Alleles containing 4 (TSER4), 5 (TSER5), and 9 (TSER9) copies of the tandem repeat have also been identified, although the effect of these alleles remains unclear. Preliminary data have suggested that stage III colorectal cancer patients with the TSER3/TSER3 genotype do not receive the improvement in survival from adjuvant 5-FU observed in patients with the TSER3/TSER2 or TSER2/TSER2 genotype. A poor response rate to 5-FU for neoadjuvant rectal or metastatic colorectal disease is also apparent in TSER3/TSER3 patients. This has significant clinical implications because TSER3/TSER3 occurs in 30% of Caucasian patients. Ethnic variation also exists in the TSER, with Asian populations having significantly higher frequency of TSER3 than other world populations. Prospective confirmation of the impact of TSER on outcome, after TS-targeted chemotherapy, will define the utility of pharmacogenetics to optimize the selection of 5-FU therapy for colorectal cancer.