Future challenges in the clinical development of thymidylate synthase inhibitor compounds.

Thymidylate synthase (TS) is a folate-dependent enzyme that plays a critical role in providing the thymidylate nucleotide precursors essential for DNA biosynthesis. Given the increased metabolic demands that accompany malignant cell proliferation, it has been well-appreciated that TS represents an important target for cancer therapy. The fluoropyrimidines were the first class of agents to be directed against TS. As a result of extensive preclinical and clinical investigations, new inhibitor compounds of TS were subsequently designed and developed. This class of antifolate analogues includes ZD1694 (Tomudex), LY231514 (MTA), BW1843U89, ZD9331, AG331, and AG337. Although each of these analogues acts to inhibit TS, the data from both preclinical and early clinical studies suggest that they may each have a different spectrum of tumors against which they are active. In this commentary, an update of the current status of TS inhibitor compounds is presented. Finally, the future challenges that lie ahead in the clinical development with specific focus on identifying those critical factors that will determine the spectrum of antitumor activity and therapeutic selectivity of this interesting class of compounds are discussed.