Methotrexate, action mechanism

Mechanism of Action An antidote to folic acid antagonists that may limit methotrexate action on normal cells by competing with methotrexate for the same transport processes into the cells Therapeutic Effect Reverses toxic effects of folic acid antagonists. Reverses folic acid deficiency. 

Uga, H., Knramoii, C., Ohta, A., et al. (2006). A new mechanism of methotrexate action revealed by target screening with affinity beads. Mol Pharmacol, 70, 1832-1839. 

Different biochemical mechanisms of acquired resistance to methotrexate can affect each known step in methotrexate action, including (I) impaired transport of methotrexate into cells ... 

Let s start with three examples of antitumor drugs that work by the inhibition of DNA synthesis methotrexate (MTX, Methopterin), 5-fluorouracil (Fluril), and 6-mercaptopurine (Purinethol). These are all old cancer drags, marketed under numerous trade names, including those indicated above. Although the mechanism of action of each one is different, at the end of the day they all inhibit DNA synthesis. 

Pharmacology The mechanism of action in RA is unknown it may affect immune function. Methotrexate inhibits dihydrofolic acid reductase and interferes with DNA synthesis, repair, and cellular replication. 

In Fig. 1 various targets of some important cytostatic agents are depicted. Their main mechanisms of action can be briefly summarized as follows. Pentostatin blocks purine nucleotides by inhibiting adenosine deaminase. 6-Mercaptopurine and 6-thioguanine inhibit purine ring biosynthesis and they inhibit nucleotide interconversions. Methotrexate by inhibiting dihydrofolate reduction blocks thymidine monophosphate and purine synthesis. 5-Fluorouracil also blocks thymidine monophosphate synthesis. Dactinomycin, daunorubicin, doxorubicin and mitoxantrone intercalate with DNA and inhibit RNA synthesis. L-asparaginase deaminates... 

Methotrexate is a folic acid analogue. Its mechanism of action is based on the inhibition of dihydrofolate reductase. Inhibition of dihydrofolate reductase leads to depletion of the tetrahydrofolate cofactors that are required for the synthesis of purines and thymidylate (see Fig. 2). Enzymes that are required for purine and thymidylate synthesis are also directly inhibited by the polyglutamates of methotrexate which accumulate with dihydrofolate reductase inhibition. The mechanisms that can cause resistance include decreased transport of methotrexate into the tumor cells, a decreased affinity of the antifolate for dihydrofolate reductase, increased concentrations of intracellular dihydrofolate reductase and decreased thymidylate synthetase activity. 

Its mechanism of action is based on intercalation in the minor groove of double stranded DNA, interference with RNA polymerase and with topoiso-merase II. Its primary indications are rhabdomyosarcoma and Wilms tumor in children. In combination with methotrexate, it is used in the treatment of choriocarcinoma. 

Methotrexate s principal mechanism of action at the low doses used in the rheumatic diseases probably relates to inhibition of aminoimidazolecarboxamide ribonucleotide (AICAR) transformylase and thymidylate synthetase, with secondary effects on polymorphonuclear chemotaxis. There is some effect on dihydrofolate reductase and this affects lymphocyte and macrophage function, but this is not its principal mechanism of action. Methotrexate has direct inhibitory effects on proliferation and stimulates apoptosis in immune-inflammatory cells. Additionally, inhibition of proinflammatory cytokines linked to rheumatoid synovitis has been shown, leading to decreased inflammation seen with rheumatoid arthritis. 

The principal mechanism of action is inhibition of dihydrofolate reductase, an enzyme important in the production of thymidine and purines. At the high doses used for chemotherapy, methotrexate inhibits cellular proliferation. However, at the low doses used in the treatment of inflammatory bowel disease (12-25 mg/wk), the antiproliferative effects may not be evident. Methotrexate may interfere with the inflammatory actions of interleukin-1. It may also stimulate increased release of adenosine, an endogenous anti-inflammatory autacoid. Methotrexate may also stimulate apoptosis and death of activated T lymphocytes. 

Mechanism of Action. The pharmacology of methotrexate is described in Chapter 36. This drug acts as an antimetabolite that interferes with the production of DNA and RNA precursors in rapidly proliferating cells. This interference produces a general inhibition of the replication of lymphocytes inherent in the immune response. 

Mechanism of action of methotrexate and the effect of administration of leucovorin [FH2 = dihydrofolate FH4 = tetrahydrofolate]. 

The benefits are reduced joint pain, swelling and stiffness, and less joint damage in the long term. The principal mechanism which is important in achieving these results is not rmderstood with certainty for any of the DMARDs, although some actions are known, e.g. methotrexate and sulpha-salazine are primarily antifolate drugs, whilst ciclo-sporin affects T-cell function. 

Cronstein BN. Molecular therapeutics. Methotrexate and its mechanism of action. Arthritis Rheum 1996 39(12) 1951-60. 

Drug Delivery - The most widely studied method of reducing toxicity of antitumor agents has continued to be encapsulation in liposomes. The mechanism of drug toxicity reduction and pharmacokinetics of liposome-encapsulated drugs have been reviewed.Methotrexate in lipid vesicles enhanced absorption in tumor cells vitro and resulted in 80% tumor reduction in mice bearing a P1798 lymphosarcoma, a tumor resistant to the same amount of free methotrexate. The unstable nature of aqueous suspensions of CCNU was overcome and the duration of dru action increased, when it was formulated with phosphatidyl choline. Tar-... 

Traditional medical therapies for Crohn s disease include sulfasalazine and corticosteroids. These are pluripotent, reducing the production of inflammatory mediators and cytokines, although the complex and multiple mechanisms remain incompletely understood. Novel therapies related to newer aminosalicylate preparations such as balsalazide (colazide) or olsalazine (dipentum) newer corticosteroids such as budesonide immunomodulators such as azathioprine, 6-mercaptopurine, or methotrexate and antibiotics such as metronidazole are aimed at more specific delivery of active compounds to the site of disease, reduction of systemic absorption and side effects, and modulation of more focal targets within the immune response and the action of specific proinflammatory cytokines. 

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