Folate antagonists methotrexate

Folate antagonists Methotrexate Ralitrexed Pemetrexed (alimta)... 

Vincristine has been shown to enhance the accumulation of the folate antagonist methotrexate in murine leukemia cells, and the enhancement has been shown to involve inhibition of a specific efflux route for methotrexate (25) the suggestion has been made that the effect of vincristine on methotrexate efflux may be related to alterations of cell membrane electrical activity that appear to occur when cells are treated with vincristine. In this connection, it is worth mentioning that association of tubulin with membrane structures from bovine brain has been described 25a). Both vinblastine and vincristine have been reported to enhance the accumulation of the folate antagonist methotrexate in human leukemic cells (S) there is no evidence, however, to indicate that this interaction has significance in a clinical setting. 

Figure 10.1 also shows the structures of the folate antagonist methotrexate (iV -methyl aminopterin) and the pterin coenzymes tetrahydrobiopterin (Section 10.4) and molybdopterin (Section 10.5). 

Figure 10.1. Folate vitamers, the folate antagonist methotrexate, molybdopterln, and tetrahydrobiopterin. Relative molecular masses (Mr) tetrahydrofolic acid, 445.4 methotrexate, 454.5 and tetrahydrobiopterin, 290.3.

Folate antagonists (eg, methotrexate and certain antiepileptics) are used ia treatment for various diseases, but their adininistration can lead to a functional folate deficiency. Folate utilization can be impaired by a depletion of ziac (see Zinc compounds). In humans, the intestinal bmsh border folate conjugase is a ziac metaHoenzyme (72). One study iadicates that the substantial consumption of alcohol, when combiaed with an iaadequate iatake of folate and methionine, may iacrease the risk of colon cancer (73). Based on this study, it is recommended to avoid excess alcohol consumption and iacrease folate iatake to lower the risk of colon cancer. 

These are pyrimidine derivatives and are effective because of differences in susceptibility between the enzymes in humans and in the infective organism. Anticancer agents based on folic acid, e.g. methotrexate, inhibit dihydrofolate reductase, but they are less selective than the antimicrobial agents and rely on a stronger binding to the enzyme than the natural substrate has. They also block pyrimidine biosynthesis. Methotrexate treatment is potentially lethal to the patient, and is usually followed by rescue with folinic acid (A -formyl-tetrahydrofolic acid) to counteract the folate-antagonist action. The rationale is that folinic acid rescues normal cells more effectively than it does tumour cells. 

Many drugs interact with folate to affect its absorption, antagonize its biochemical activity, or increase its loss from the body. These drugs include ethanol, phenytoin, and oral contraceptives. Salicylates can compete with foUc acid for plasma protein binding. Methotrexate, a cytotoxic agent, is a folate antagonist that inhibits the biosynthesis of this coenzyme. 

Methotrexate (53-6), one of the first modified pteridines investigated as a folate antagonist, is still used quite extensively in the chemotherapy of cancer and to a minor extent in other indications calling for cytotoxic agents. 

The main folate antagonist is methotrexate, an analogue of folic acid. Methotrexate competitively inhibits dihydrofolate reductase, the enzyme responsible for the synthesis of purine and pyramidine from folic acid. Trimetrexate, a methotrexate analogue, is useful in treating methotrexate-resistant tumours. It is also used to treat Pneumocystis carinii infections. Methotrexate is usually given orally, but may also be given intravenously or intrathecally. In addition to its use in cancer therapy, it is used in the treatment of psoriasis. Methotrexate can cause an obstructive nephropathy due to its precipitation in the renal calyx. 

Another way to reduce the supply of deoxynucleotides for cell replication is to target the reduction of dihydrofolate to tetrahydrofo-late. Folate antagonists are used in antimicrobial and anticancer chemotherapy. These compounds are competitive inhibitors of dihydrofolate reductase because they resemble the natural substrate. For example, methotrexate is used in antitumor therapy. 

The search for better tolerated folate antagonist antitumor agents continues to produce yet more variants on methotrexate [see pemetrexed (46) for structure]. The analogue pralatrexate (202) retains most of the features of the prototype, but replaces the side-chain tertiary amine by a... 

Methotrexate is a valuable drug in the treatment of many rapidly growing tumors, such as those in acute leukemia and choriocarcinoma, a cancer derived from placental cells. However, methotrexate kills rapidly replicating cells whether they are malignant or not. Stem cells in bone marrow, epithelial cells of the intestinal tract, and hair follicles are vulnerable to the action of this folate antagonist, accounting for its toxic side effects, which include weakening of the immune system, nausea, and hair loss. 

Drugs. Antiepilepsy drugs, particularly phenytoin, primidone and phenobarbital, occasionally cause a macrocytic anaemia that responds to folic acid. This may be due to enzyme induction by the antiepileptics increasing the need for folic acid to perform hydroxylation reactions (see Epilepsy) but other factors such as reduced absorption may be involved. Administration of folic acid causes a recurrence of seizures in some patients. Some anti-malarials, e.g. pyrimethamine, may interfere with conversion of folates to the active tetrahydrofolic acid, causing macrocytic anaemia. Methotrexate, another folate antagonist, may cause a megaloblastic anaemia especially when used long-term for leukaemia, rheumatoid arthritis or psoriasis. 

DIHYDROFOLATE REDUCTASE INHIBITORS have as a target the enzyme dihydrofolate reductase, and are known as folate antagonists. These include anttcancer agents ( antimetabolites ) such as methotrexate, antibacterial AGENTS such as trimethoprim, and the antiprotozoals pyrimethamine and proguanil (which are used to treat malaria). Folate is required for synthesis of purine nucleotides, which in turn are essential for DNA synthesis and cell division. In mammals it is necessary to convert body folates, through two separate enzyme-catalysed reduction... 

Folate analogues, such as methotrexate (Figure 27-3), are folate antagonists. They block production of FH2 and FH4 by dihydrofolate reductase and lead to diminished purine biosynthesis (inhibition of reactions 3 and 9 in Figure 27-8). Methotrexate also affects metabolism of amino acids and pyrimidine (inhibition of thymidylate synthesis) and inhibits DNA, RNA, and protein synthesis. It is effective in the treatment of breast cancer, cancer of the head and neck, choriocarcinoma, osteogenic sarcoma, and acute forms of leukemia. High doses of methotrexate can be tolerated provided that the patient also receives folinic... 

Vitamin deficiency can result from treatment with certain drags. Thus, destruction of intestinal microorganisms by antibiotic therapy can produce symptoms of vitamin K deficiency. Isoniazid, used to treat tuberculosis, is a competitive inhibitor of pyridoxal kinase, which is needed to produce pyridoxal phosphate. Isoniazid can produce symptoms of pyridoxine deficiency. To prevent this, pyridoxine is often incorporated into isoniazid tablets. Methotrexate and related folate antagonists act by competitively inhibiting dihydrofolate reductase (Chapter 27). 

Methotrexate (4-amino-10-methylpteroylglutamic acid) was one of the first folate antagonists to be used clinically and it has now heen in use for more than 30 years. It is useful for the treatment of a number of malignancies and... 

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