Thymidylate synthase: a target for combination therapy and determinant of chemotherapeutic response in colorectal cancer.

In this review, we describe the role of thymidylate synthase (TS) as a determinant of chemotherapeutic response. TS is an essential enzyme for the de novo synthesis of thymidylate and subsequent DNA synthesis. TS has been used as a target for cancer chemotherapy in the development of fluoropyrimidines such as 5-fluorouracil (5FU) and 5-fluorodeoxyuridine and novel folate-based TS inhibitors such as ZD1694 (Tomudex, Raltitrexed), LY231514, AG337 (Thymitaq) and GW1843U89. All these antifolates have different transport mechanisms and various polyglutamylation and accumulation patterns which are all important for drug sensitivity. An update of clinical studies with TS inhibitors (antifolate-based TS inhibitors and 5FU combination studies) will be given and new perspectives for clinical development will be discussed. The prognostic or predictive value of TS (in vitro, in vivo and in patients) will be reviewed, focusing on colorectal cancer.