antifolate

Image:Methotrexate skeletal.svg|Methotrexate

Image:Pemetrexed.svg|Pemetrexed

Image:Raltitrexed.svg|Raltitrexed

Image:Pralatrexate.png|Pralatrexate

Many are primarily DHFR inhibitors, but raltitrexed is an inhibitor of thymidylate synthase, and pemetrexed inhibits both and a third enzyme.

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.

File:Folic acid.svg

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.{{cite journal |vauthors=Morgan SL, Baggott JE, Alarcon GS | title=Methotrexate in rheumatoid arthritis: folate supplementation should always be given | journal=BioDrugs | volume=8 | issue=1 | year=1997 | pages=164–75 | pmid=18020507|doi=10.2165/00063030-199708030-00002| s2cid=26003509 }}{{cite journal |vauthors=Morgan SL, Baggott JE, Lee JY, Alarcon GS |title=Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during long-term, low-dose methotrexate therapy for rheumatoid arthritis: Implications for cardiovascular disease prevention | journal=Journal of Rheumatology | volume=25|issue=3 | year=1998 | pages=441–6 | pmid=9517760}}

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 of 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 reductase can overcome the drugs inhibition.

Many new drugs are under development to reduce antifolate drug resistance.{{cite journal |author=Takimoto CH|title=New Antifolates: Pharmacology and Clinical Applications |journal=Oncologist |volume=1 |issue=1 & 2 |pages=68–81|year=1996|doi=10.1634/theoncologist.1-1-68 |pmid=10387971 |url=http://theoncologist.alphamedpress.org/cgi/pmidlookup?view=long&pmid=10387971|doi-access=free }}{{cite journal |vauthors=Gangjee A, Jain HD, Kurup S |title=Recent advances in classical and non-classical antifolates as antitumor and antiopportunistic infection agents: part I |journal=Anti-Cancer Agents Med Chem |volume=7 |issue=5 |pages=524–42 |date=September 2007 |pmid=17896913 |doi=10.2174/187152007781668724 |url=http://www.bentham-direct.org/pages/content.php?ACAMC/2007/00000007/00000005/0005W.SGM |url-status=usurped |archive-url=https://archive.today/20130414070702/http://www.bentham-direct.org/pages/content.php?ACAMC/2007/00000007/00000005/0005W.SGM |archive-date=2013-04-14 |url-access=subscription }}

The name antifolate usually refers to drugs whose folate antagonism is intentional. In contrast, there are some other drugs, of several drug classes, that antagonize folate incidentally, as an adverse effect, whether mildly or heavily. This effect is often not noticeable except when it causes a neural tube defect in a fetus carried by a woman taking the medication. Such drugs include some anticonvulsants (valproic acid, carbamazepine, phenobarbital, phenytoin, and primidone) and trimethoprim. Lamotrigine is also an anticonvulsant with known (from in vitro testing) weak anti-folate effects.{{cite book|last1=Brunton|first1=Laurence|title=Goodman & Gilman's pharmacological basis of therapeutics.|date=2011|publisher=McGraw-Hill|location=New York|isbn=978-0-07-162442-8|edition=12th}}

• Sulfonamides, a class of antimicrobials that work by inhibiting folate biosynthesis.

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• {{MeshName|Antifolates}}

{{Sulfonamides and trimethoprim}}

{{Chemotherapeutic agents}}

{{Antimalarials}}

{{Purinergics}}

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