Antifolates are drugs that impair the function of folic acids.[1] Many are used in cancer chemotherapy, some are used as antibiotics or antiprotozoal agents.
A well-known example is methotrexate. This is a folic acid analogue, and owing to structural similarity with it binds and inhibits the enzyme dihydrofolate reductase (DHFR), and thus prevents the formation of tetrahydrofolate. Because tetrahydrofolate is essential for purine and pyrimidine synthesis, its deficiency can lead to inhibited production of DNA, RNA, and proteins (as tetrahydrofolate is also involved in the synthesis of amino acids serine and methionine).
Since antifolates interfere with metabolism (of nucleotides), they are categorized as antimetabolites.
Other antifolates include trimethoprim, pyrimethamine, and pemetrexed.
Many are primarily DHFR inhibitors, but raltitrexed is an inhibitor of thymidylate synthase, and pemetrexed inhibits both and a third enzyme.
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Low-dose methotrexate is used to treat a wide variety of non-cancerous diseases such as rheumatoid arthritis, lupus, scleroderma, psoriasis, asthma, sarcoidosis, primary biliary cirrhosis, polymyositis, and inflammatory bowel disease.[2]
Antifolates act specifically during DNA and RNA synthesis, and thus are cytotoxic during the S-phase of the cell cycle. Thus, they have a greater toxic effect on rapidly dividing cells (such as malignant and myeloid cells, and GI & oral mucosa), which replicate their DNA more frequently, and thus inhibits the growth and proliferation of these non-cancerous cells as well as causing the side-effects listed.
The antifolate action specifically targets the fast-dividing cells, and tend to have adverse effects on the bone marrow, skin, and hair. As folate is vital in the first trimester of pregnancy for healthy fetal development, the use of antifolates is strongly contraindicated in pregnancy and carries significant teratogenic risk.
Low doses of methotrexate can deplete folate stores and cause side-effects that are similar to folate deficiency. Both high-folate diets and supplemental folic acid may help reduce the toxic side-effects of low-dose methotrexate without decreasing its effectiveness.[3][4] Anyone taking low-dose methotrexate for the health problems listed above should consult with a physician about the need for a folic acid supplement.
While the role in folate as a cancer treatment is well established, its long-term effectiveness is diminished by cellular response. In response to decreased tetrahydrofolate (THF), the cell begins to transcribe more DHF reductase, the enzyme that reduces DHF to THF. Because methotrexate is a competitive inhibitor of DHF reductase, increased concentrations of DHF eductase can overcome the drugs inhibition.
Many new drugs are under development to reduce antifolate drug resistance.[5][6]
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