Thymidylate synthase inhibitors as anticancer agents: from bench to bedside.

摘要: Thymidylate synthase (TS) is a folate-dependent enzyme that catalyzes the reductive methylation of 2'-deoxyuridine-5'-monophosphate to 2'-deoxythymidine-5'-monophosphate. This pathway provides sole intracellular de novo source 2'-deoxythymidine-5'-triphosphate; therefore, TS represents critical target in cancer chemotherapy. 5-Fluorouracil (5-FU) was synthesized 1957 and first class antineoplastic agents be developed as inhibitors TS. While 5-FU has been widely used treat various human malignancies, its overall clinical efficacy limited. Therefore, significant efforts have focused on design novel, more potent inhibitor compounds These fall into two main categories: folate analogs nucleotide analogs. Five antifolate are currently being evaluated clinic: raltitrexed, pemetrexed, nolatrexed, ZD9331, GS7904L. Our laboratory identified novel mechanism resistance develops compounds, namely drug-mediated acute induction new synthesis; this directly controlled at translational level. The ability cells acutely induce expression may represent for development cellular drug resistance. future success clinic depend strategies selectively inhibit combination therapies overcome