The antifolates were the first class of antimetabolites to enter the clinics 65 years ago. Their mechanism of action is due to the disruption of the metabolic pathways that require one-carbon moieties supplied by the B9 folate vitamins which they resemble. While renewing tissues of the bone marrow and intestinal tract are also folate-dependent and are sites of antifolate toxicity, the clinical utility of antifolates was established with the identification of doses and schedules of administration that provided sufficient selectivity to make these drugs effective in the treatment of cancer as well as inflammatory disorders.
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