Thymidylate synthase inhibitors

Despite the development of a range of exciting novel agents in cancer therapy, thymidylate synthase (TS) inhibitors remain pivotal in the management of many malignancies. Indeed, it can be said that TS inhibitors represent the first group of selectively targeted therapies used in cancer, since in the late 1950s the critical role of TS and thymidine to DNA synthesis were recognized and led to the rational development of fluoropyrimidines (FPs). Research in the last few years has expanded our knowledge of the TS gene and protein, and of the mechanism by which TS inhibition induces cell death, as well as the mechanism of action of various inhibitors of TS. This chapter highlights new insights and developments in the understanding of TS and its regulation, and in the preclinical and clinical development of TS inhibitors in the last 1–2 years. The most notable new information relates to molecular factors allowing better prediction of outcome from TS inhibition, use of FP-based combinations in adjuvant therapy of colorectal and lung cancers, and the increasing range of clinical applications for both antifolate TS inhibitors and fluoropyrimidines.