Terence R. Jones

Thymidylate Synthetase Inhibitors: Experimental and Clinical Aspects

The enzyme thymidylate synthetase (TS) which accomplishes the methylation of deoxyuridine monophosphate to thymidine monophosphate has been of interest ever since its discovery in 1957 [1]. Its crucial role in the synthesis of the only nucleotide required exclusively for DNA synthesis makes it an obvious target for antimetabolite attack. The discovery by Cohen [2] that 5-fluorodeoxyuridine monophosphate (FdUMP), a metabolite of the antipyrimidines 5-fluorouracil and 5-fluorodeoxyuridine, was a potent inhibitor of TS, coupled with the documentation of clinical antitumour activity for this drug ensured the continuing studies both of TS and antipyrimidines. The detailed and painstaking studies of the nature of the tight binding of FdUMP to TS in the presence of the cofactor 5,10-CH2FH4, to produce a stable ternary complex have given us enormous insights into the mechanism of TS catalysis and have allowed the rational design of further TS-inhibitory uracil derivatives. The inhibition of TS by FdUMP was accepted for many years as the main basis for the cytotoxicity of the fluorinated pyrimidines, and only recently have the incorporations of these molecules into nucleic acids been fully considered as alternative or contributory cytotoxic events. The knowledge that FU has cytotoxic actions unrelated to TS inhibition implies that an inhibition of TS uncomplicated by other actions has not been evaluated as an antitumour event.