FUTURE CHALLENGES IN THE CLINICAL DEVELOPMENT OF THYMIDYLATE SYNTHASEINHIBITOR COMPOUNDS

Thymidylate synthase (TS) is a folate-dependent enzyme that plays a cr itical role in providing the thymidylate nucleotide precursors essenti al for DNA biosynthesis. Given the increased metabolic demands that ac company malignant cell proliferation, it has been well-appreciated tha t TS represents an important target for cancer therapy. The fluoropyri midines were the first class of agents to be directed against TS. As a result of extensive preclinical and clinical investigations, new inhi bitor compounds of TS were subsequently designed and developed. This c lass of antifolate analogues includes ZD1694 (Tomudex), LY231514 (MTA) , BW1843U89, ZD9331, AG331, and AG337. Although each of these analogue s acts to inhibit TS, the data from both preclinical and early clinica l studies suggest that they may each have a different spectrum of tumo rs against which they are active. In this commentary, an update of the current status of TS inhibitor compounds is presented. Finally, the f uture challenges that lie ahead in the clinical development with speci fic focus on identifying those critical factors that will determine th e spectrum of antitumor activity and therapeutic selectivity of this i nteresting class of compounds are discussed.