Cancer research: from folate antagonism to molecular targets.

The antifolates aminopterin and methotrexate have two firsts in the treatment of malignancy. Aminopterin was the first drug reported to cause remissions in children with acute lymphocytic leukaemia, and methotrexate (MTX), the antifolate that has supplemented aminopterin in the clinic, was the first drug that was shown to be curative for patients with a solid tumour, choriocarcinoma. More than 50 years after its introduction in the clinic, MTX is still being used and studied. The role of dihydrofolate reductase (DHFR), the principal target of aminopterin, has been studied extensively, and DHFR gene amplification and mutations have been implicated in drug resistance. Recent research focusses on studies of the translational regulation of DHFR and transfer of mutant DHFR and other drug resistance genes by viral vectors to protect haematopoietic cells. Based upon the detailed understanding of the mechanism of action of antifolates, both as inhibitors of DHFR and thymidylate syntase (TS), new agents have been developed that show effectiveness in the treatment of human malignancies. MTX remains a potent and widely used agent.