Antifolates

Antifolates are a class of antimetabolite drugs that disrupt folate-dependent one-carbon metabolism essential for DNA synthesis and repair. By depleting cellular folate cofactors, they impair synthesis of thymidylate and purine nucleotides, preferentially affecting rapidly dividing cells.

Most antifolates inhibit enzymes in the folate cycle. Dihydrofolate reductase (DHFR) inhibitors, such as methotrexate and, in bacteria, trimethoprim, block regeneration of tetrahydrofolate. Other agents, such as pemetrexed and pralatrexate, inhibit several folate-dependent enzymes including DHFR, thymidylate synthase (TS), and formyltransferases involved in purine synthesis. By blocking these steps, cells cannot synthesize DNA effectively, leading to S-phase arrest and apoptosis. Leucovorin (folinic acid) rescue can mitigate toxicity by bypassing the need for DHFR.

Clinical use varies by agent. Methotrexate is used in a range of cancers and in autoimmune diseases such as rheumatoid arthritis; pemetrexed is used for mesothelioma and non-small cell lung cancer; pralatrexate has approvals for certain lymphomas; trimethoprim-sulfamethoxazole is an antibiotic combination targeting bacterial DHFR; raltitrexed is a TS inhibitor used in some colorectal cancers. Antifolates are commonly employed in combination regimens to enhance efficacy and manage resistance, with dose adjustments to balance anti-tumor activity against toxicity.

Pharmacology and resistance are influenced by cellular uptake and retention. Transporters and the reduced folate carrier mediate entry, while polyglutamation by folylpolyglutamate synthase increases intracellular retention and potency. Resistance can arise from reduced drug uptake, DHFR amplification or mutation, and changes in folate pathway enzymes. Common toxicities include myelosuppression, mucositis, hepatotoxicity, nephrotoxicity, and teratogenic effects.