Antifolate

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Dihydrofolate reductase (DHFR) Dihydrofolate reductase 1DRF.png
Dihydrofolate reductase (DHFR)
Folic acid Folic acid.svg
Folic acid

Antifolates are a class of antimetabolite medications that antagonise (that is, block) the actions of folic acid (vitamin B9). [1] Folic acid's primary function in the body is as a cofactor to various methyltransferases involved in serine, methionine, thymidine and purine biosynthesis. Consequently, antifolates inhibit cell division, DNA/RNA synthesis and repair and protein synthesis. Some such as proguanil, pyrimethamine and trimethoprim selectively inhibit folate's actions in microbial organisms such as bacteria, protozoa and fungi. The majority of antifolates work by inhibiting dihydrofolate reductase (DHFR). [2]

Contents

Comparison of available agents

DrugClassPharmacologic targetMyelosuppressive effectUS pregnancy categoryIndicationsNotable adverse effects
Methotrexate [3] Antineoplastic & immunosuppressantMammalian DHFR+++XMalignancies (esp. haematologic malignancies and osteosarcoma), ectopic pregnancy and autoimmune conditions (esp. rheumatoid arthritis, psoriasis, Granulomatosis with polyangiitis, Goodpasture syndrome, etc.)Kidney or liver failure, Stevens–Johnson syndrome, toxic epidermal necrolysis, infection, aplastic anaemia, opportunistic infections and GI effects.
Pemetrexed [4] AntineoplasticMammalian DHFR, TS, GARFT+++D Non-small cell lung carcinoma & mesothelioma Nausea, vomiting, dyspnoea, constipation, chest pain, diarrhoea, weight loss, stomatitis, rash, fever, peripheral neuropathy, dehydration, kidney failure, Stevens–Johnson syndrome, toxic epidermal necrolysis and erythema multiforme.
Proguanil [5] AntimalarialProtozoal DHFR+/-CMalaria, prevention and treatmentAbdominal pain, headaches, increased LFTs, myalgia, nausea, opportunistic infections, diarrhoea, vomiting, etc. Less commonly Stevens–Johnson syndrome, toxic epidermal necrolysis, agranulocytosis, liver failure, anaphylaxis, etc.
Pyrimethamine [6] AntiprotozoalProtozoal DHFR+/-CMalaria, toxoplasmosis and pneumocystis jiroveci pneumonia.Stevens–Johnson syndrome, toxic epidermal necrolysis, agranulocytosis and aplastic anaemia.
Trimethoprim [7] Broad-spectrum antimicrobialMicrobial DHFR+/-CNumerous (especially when in combination with the sulfonamide, sulfamethoxazole); treatment & prophylaxis for pneumocystis jiroveci pneumonia, malaria and toxoplasmosis. Treatment of melioidosis, shigellosis, listeria, urinary tract infections, acute infectious exacerbations of chronic bronchitis, infection prophylaxis in HIV-positive individuals, cyclospora protozoa, etc.Stevens–Johnson syndrome, toxic epidermal necrolysis, agranulocytosis and aplastic anaemia.

Mechanism

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.

Limitations

Side-effects

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. [8] [9] Anyone taking low-dose methotrexate for the health problems listed above should consult with a physician about the need for a folic acid supplement.

Resistance

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. [10] [11]

Drugs that incidentally antagonize folate

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. [12]

See also

Related Research Articles

<span class="mw-page-title-main">Folate</span> Vitamin B9; nutrient essential for DNA synthesis

Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and storage. Folate is required for the body to make DNA and RNA and metabolise amino acids necessary for cell division. As the human body cannot make folate, it is required in the diet, making it an essential nutrient. It occurs naturally in many foods. The recommended adult daily intake of folate in the U.S. is 400 micrograms from foods or dietary supplements.

<span class="mw-page-title-main">Dihydrofolate reductase</span> Mammalian protein found in Homo sapiens

Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as an electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in 1-carbon transfer chemistry. In humans, the DHFR enzyme is encoded by the DHFR gene. It is found in the q14.1 region of chromosome 5.

<span class="mw-page-title-main">Trimethoprim</span> Antibiotic

Trimethoprim (TMP) is an antibiotic used mainly in the treatment of bladder infections. Other uses include for middle ear infections and travelers' diarrhea. With sulfamethoxazole or dapsone it may be used for Pneumocystis pneumonia in people with HIV/AIDS. It is taken orally.

<span class="mw-page-title-main">Methotrexate</span> Chemotherapy and immunosuppressant medication

Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leukemia, lung cancer, lymphoma, gestational trophoblastic disease, and osteosarcoma. Types of autoimmune diseases it is used for include psoriasis, rheumatoid arthritis, and Crohn's disease. It can be given by mouth or by injection.

<span class="mw-page-title-main">Acetazolamide</span> Chemical compound

Acetazolamide, sold under the trade name Diamox among others, is a medication used to treat glaucoma, epilepsy, altitude sickness, periodic paralysis, idiopathic intracranial hypertension, heart failure and to alkalinize urine. It may be used long term for the treatment of open angle glaucoma and short term for acute angle closure glaucoma until surgery can be carried out. It is taken by mouth or injection into a vein. Acetazolamide is a first generation carbonic anhydrase inhibitor and it decreases the ocular fluid and osmolality in the eye to decrease intraocular pressure.

<span class="mw-page-title-main">Trimethoprim/sulfamethoxazole</span> Combination of 2 antibiotic drugs

Trimethoprim/sulfamethoxazole, sold under the brand name Bactrim among others, is a fixed-dose combination antibiotic medication used to treat a variety of bacterial infections. It consists of one part trimethoprim to five parts sulfamethoxazole. It is used to treat urinary tract infections, methicillin-resistant Staphylococcus aureus (MRSA) skin infections, travelers' diarrhea, respiratory tract infections, and cholera, among others. It is used both to treat and prevent pneumocystis pneumonia and toxoplasmosis in people with HIV/AIDS and other causes of immunosuppression. It can be given orally or intravenous infusion.

<span class="mw-page-title-main">Folinic acid</span> Derivative of folic acid used in cancer treatment

Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to treat folate deficiency that results in anemia, and methanol poisoning. It is taken by mouth, injection into a muscle, or injection into a vein.

<span class="mw-page-title-main">Sulfamethoxazole</span> Chemical compound

Sulfamethoxazole is an antibiotic. It is used for bacterial infections such as urinary tract infections, bronchitis, and prostatitis and is effective against both gram negative and positive bacteria such as Listeria monocytogenes and E. coli.

<span class="mw-page-title-main">Aminopterin</span> Chemical compound

Aminopterin, the 4-amino derivative of folic acid, is an antineoplastic drug with immunosuppressive properties often used in chemotherapy. Aminopterin is a synthetic derivative of pterin. Aminopterin works as an enzyme inhibitor by competing for the folate binding site of the enzyme dihydrofolate reductase. Its binding affinity for dihydrofolate reductase effectively blocks tetrahydrofolate synthesis. This results in the depletion of nucleotide precursors and inhibition of DNA, RNA, and protein synthesis.

<span class="mw-page-title-main">Pemetrexed</span> Chemical compound

Pemetrexed, sold under the brand name Alimta among others, is a chemotherapy medication for the treatment of pleural mesothelioma and non-small cell lung cancer (NSCLC)..

An antimetabolite is a chemical that inhibits the use of a metabolite, which is another chemical that is part of normal metabolism. Such substances are often similar in structure to the metabolite that they interfere with, such as the antifolates that interfere with the use of folic acid; thus, competitive inhibition can occur, and the presence of antimetabolites can have toxic effects on cells, such as halting cell growth and cell division, so these compounds are used as chemotherapy for cancer.

<span class="mw-page-title-main">Proguanil</span> Chemical compound

Proguanil, also known as chlorguanide and chloroguanide, is a medication used to treat and prevent malaria. It is often used together with chloroquine or atovaquone. When used with chloroquine the combination will treat mild chloroquine resistant malaria. It is taken by mouth.

<span class="mw-page-title-main">4-Aminosalicylic acid</span> Anti-tuberculosis and anti-inflammatory drug

4-Aminosalicylic acid, also known as para-aminosalicylic acid (PAS) and sold under the brand name Paser among others, is an antibiotic primarily used to treat tuberculosis. Specifically it is used to treat active drug resistant tuberculosis together with other antituberculosis medications. It has also been used as a second line agent to sulfasalazine in people with inflammatory bowel disease such as ulcerative colitis and Crohn's disease. It is typically taken by mouth.

<span class="mw-page-title-main">Pyrimethamine</span> Medication

Pyrimethamine, sold under the brand name Daraprim among others, is a medication used with leucovorin to treat the parasitic diseases toxoplasmosis and cystoisosporiasis. It is also used with dapsone as a second-line option to prevent Pneumocystis jiroveci pneumonia in people with HIV/AIDS. It was previously used for malaria but is no longer recommended due to resistance. Pyrimethamine is taken by mouth.

<span class="mw-page-title-main">Folate deficiency</span> Abnormally low level of folate (vitamin B9) in the body

Folate deficiency, also known as vitamin B9 deficiency, is a low level of folate and derivatives in the body. Signs of folate deficiency are often subtle. A low number of red blood cells (anemia) is a late finding in folate deficiency and folate deficiency anemia is the term given for this medical condition. It is characterized by the appearance of large-sized, abnormal red blood cells (megaloblasts), which form when there are inadequate stores of folic acid within the body.

<span class="mw-page-title-main">Raltitrexed</span> Chemical compound

Raltitrexed is an antimetabolite drug used in cancer chemotherapy. It is an inhibitor of thymidylate synthase, and is manufactured by AstraZeneca.

<span class="mw-page-title-main">Tetrahydrofolic acid</span> Chemical compound

Tetrahydrofolic acid (THFA), or tetrahydrofolate, is a folic acid derivative.

<span class="mw-page-title-main">Dihydrofolate reductase inhibitor</span> Cellular enzyme inhibitor

A dihydrofolate reductase inhibitor is a molecule that inhibits the function of dihydrofolate reductase, and is a type of antifolate.

Sulfadoxine/pyrimethamine, sold under the brand name Fansidar, is a combination medication used to treat malaria. It contains sulfadoxine and pyrimethamine. For the treatment of malaria it is typically used along with other antimalarial medication such as artesunate. In areas of Africa with moderate to high rates of malaria, three doses are recommended during the second and third trimester of pregnancy.

<span class="mw-page-title-main">June Biedler</span> American scientist

June Biedler was an American scientist primarily known for her discovery of proteins that lead to resistance of cancer cells to chemotherapy. Her work has been crucial for an understanding of both the development of drug resistance and also for strategies to circumvent such resistance. In addition, Biedler made important contributions to an understanding of the molecular mechanisms of neuroblastoma development, particularly of the role of the N-myc oncogene in the genesis of neuroblastoma

References

  1. ↑ "NCI: antifolate".
  2. ↑ Ivan M. Kompis; Khalid Islam; Rudolf L. Then (2005). "DNA and RNA Synthesis: Antifolates". Chem. Rev. 105 (2): 593–620. doi:10.1021/cr0301144. PMID   15700958.
  3. ↑ "Trexall, Rheumatrex (methotrexate) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 10 January 2014.
  4. ↑ "Alimta (pemetrexed) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. 10 January 2014.
  5. ↑ "Paludrine (proguanil) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 10 January 2014.
  6. ↑ "Daraprim (pyrimethamine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 12 January 2014.
  7. ↑ "Primsol, Proloprim (trimethoprim) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 10 January 2014.
  8. ↑ Morgan SL, Baggott JE, Alarcon GS (1997). "Methotrexate in rheumatoid arthritis: folate supplementation should always be given". BioDrugs . 8 (1): 164–75. doi:10.2165/00063030-199708030-00002. PMID   18020507. S2CID   26003509.
  9. ↑ Morgan SL, Baggott JE, Lee JY, Alarcon GS (1998). "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 of Rheumatology . 25 (3): 441–6. PMID   9517760.
  10. ↑ Takimoto CH (1996). "New Antifolates: Pharmacology and Clinical Applications". Oncologist . 1 (1 & 2): 68–81. doi: 10.1634/theoncologist.1-1-68 . PMID   10387971.
  11. ↑ Gangjee A, Jain HD, Kurup S (September 2007). "Recent advances in classical and non-classical antifolates as antitumor and antiopportunistic infection agents: part I". Anti-Cancer Agents Med Chem . 7 (5): 524–42. doi:10.2174/187152007781668724. PMID   17896913. Archived from the original on 2013-04-14.
  12. ↑ Brunton, Laurence (2011). Goodman & Gilman's pharmacological basis of therapeutics (12th ed.). New York: McGraw-Hill. ISBN   978-0-07-162442-8.
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