Methotrexate is an anti-folate antitumor drug that inhibits a variety of animal tumors. Experiments have shown that this drug works by competitive inhibition of dihydrofolate reductase. Dihydrofolate reductase is an important enzyme in DNA synthesis, especially in the process of converting folic acid into tetrahydrofolate and deoxyuridine nucleoside methylation and conversion to thymidine. This drug selectively acts on the DNA synthesis phase (ie, S phase) and is a cycle-specific drug. Recently, some people believe that this product has a second role, that is, G1/S transition period, it can also inhibit the synthesis of interleukin-2 and inhibit the chemotaxis of neutrophils, so it has immunosuppressive and anti-inflammatory effects. At high doses, it also has direct toxic effects on non-proliferating cells, especially hepatocytes. CF is commonly used as an antidote in clinical practice.
The structure of methotrexate (MTX) is similar to that of folic acid. Hydrogen at the 4-position of folic acid and hydrogen at position 10 are amino and CH3 in MTX, respectively. MTX binds to dihydrofolate reductase, blocks the reduction of folic acid and dihydrofolate to activated tetrahydrofolate, thereby inhibiting intracellular carbon transfer, affecting the conversion of neomycin synthesis and deoxyuridine nucleotides to deoxythymidine Nucleotides, which hinder DNA and RNA synthesis. The concentration of MTX in plasma is 10-8 mol/L, which can effectively block the incorporation of deoxyuridine into DNA via deoxythymidine, and inhibit the concentration of purine synthesis by 10-7 mol/L. The binding of MTX to dihydrofolate reductase is reversible but strong. When the amount of dihydrofolate is 1000 times higher than that of MTX, it can resist the binding of MTX. In vitro, when MTX is lower than the concentration that completely inhibits DNA synthesis, it can induce differentiation of human chorionic epithelial cancer cells and increase production of chorionic gonadotropin. MTX is a cell cycle-specific drug, which mainly acts on S phase cells, and also has a certain effect on G1 phase, and has a retarding effect on G1/S.
Pharmacological action of methotrexate
