Methotrexate - Mechanism of Action

Mechanism of Action

Methotrexate is thought to affect cancer and rheumatoid arthritis by two different pathways. For cancer, methotrexate allosterically inhibits dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis. The affinity of methotrexate for DHFR is about one thousand-fold that of folate. DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolate. Folic acid is needed for the de novo synthesis of the nucleoside thymidine, required for DNA synthesis. Also, folate is needed for purine base synthesis, so all purine synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates, and proteins.

Methotrexate acts specifically during DNA and RNA synthesis, and thus it is cytotoxic during the S-phase of the cell cycle. It therefore has a greater toxic effect on rapidly dividing cells (such as malignant and myeloid cells, and gastrointestinal and oral mucosa), which replicate their DNA more frequently, and thus inhibits the growth and proliferation of these noncancerous cells, as well as causing the listed side effects. Facing a scarcity of dTMP, rapidly dividing cancerous cells undergo cell death via thymineless death.

For the treatment of rheumatoid arthritis, inhibition of DHFR is not thought to be the main mechanism, but rather the inhibition of enzymes involved in purine metabolism, leading to accumulation of adenosine, or the inhibition of T cell activation and suppression of intercellular adhesion molecule expression by T cells. In these cases, patients should supplement their diets with folate.

In its low-dose regimen methotrexate blocks the binding of interleukin 1 beta to the interleukin 1 receptor on target cells .