Antifolate Inhibitors of Thymidylate Synthase as Anticancer Drugs

A.      Jarmula

Abstract

Inhibitors of thymidylate synthase (TS) play an essential role in the pharmacological management of several tumors. Two antifolates, Raltitrexed and Pemetrexed, are licensed anticancer drugs, with Pemetrexed, unlike Raltitrexed, undergoing further intense clinical development. Other antifolate TS inhibitors, recently/currently tested in clinical studies, that show encouraging anticancer activities are Plevitrexed, GW7904L and Nolatrexed. A new prospect among antifolates, demonstrating a very desirable pattern of pharmacological properties, is BGC 945 that showed promising antitumor activities and has been nominated for clinical development. In this paper, apart from reviewing their biochemical and pharmacological properties, up-to-date characteristics of clinical development of all the mentioned agents are presented. In addition, trends and perspectives for developing improved antifolate inhibitors of TS and future drugs are discussed. Drug resistance is the main barrier to more effective treatment of cancers with antifolates; therefore, mechanisms of antifolate resistance and currently applied approaches to overcome it are also pointed out in the review.

Keywords: Thymidylate synthase (TS), inhibitors, antifolates, anticancer drugs, Thymidylate synthase, TS ThyA, deoxyuridylate, dUMP, 5,10-methylene-5,6,7,8-tetrahydrofolate, mTHF, thymidylate, dTMP, 7,8-dihydrofolate, DHF, 5-fluorouracil, FUra, 5-fluoro-2'-deoxyuridylate, (FdUMP), N(4)-hydroxy-dCMP, 5-fluoro congener, N(4)-OH-FdCMP, Raltitrexed, CB3717, PDDF, antifolate analogue, phase III Pan European Trial in Adjuvant Colon Cancer-1 (PETACC-1), malig-nant pleural mesothelioma, Pemetrexed, ALIMTA, MTA, LY231514, antifolate, dihydrofolate re-ductase, DHFR, aminoimidazole carboxamide ribonu-cleotide formyltransferase, Aicarft, lometrexol, PLEVITREXED, GW1843, NOLATREXED, BGC 945