Methotrexate is a medication used to treat specific cancers, like breast cancer and leukemia, and autoimmune diseases such as psoriasis and rheumatoid arthritis. The drug’s mechanism differs significantly depending on whether it is used for cancer or to control autoimmune disorders, making it a versatile therapeutic agent.
The Primary Biochemical Action
Methotrexate functions as an antimetabolite, a substance that interferes with metabolic processes. It is a folic acid antagonist, meaning it obstructs the use of folate (a B vitamin) inside cells. Its primary target is the enzyme dihydrofolate reductase, or DHFR, for which it has a binding affinity approximately 1000 times stronger than the enzyme’s natural target.
The DHFR enzyme converts dihydrofolate into tetrahydrofolate, a form required for producing nucleotides. These nucleotides, specifically purines and thymidylate, are the building blocks of DNA and RNA. By inhibiting DHFR, methotrexate halts the production of tetrahydrofolate, depleting the components needed for DNA and RNA synthesis and stopping cell replication.
Inside the cell, methotrexate is converted into a polyglutamated form, which is more potent at inhibiting DHFR and other enzymes. This conversion allows the drug to remain within the cell for a longer period, extending its effects.
Targeting Rapid Cell Division
The halt in DNA synthesis primarily impacts cells that divide rapidly. Cancer is defined by uncontrolled cell proliferation, a process that demands a constant supply of new DNA. Methotrexate starves malignant cells of the materials needed for replication, disrupting the cell cycle, particularly during the S phase when DNA synthesis occurs.
The inability to complete DNA replication can trigger apoptosis, or programmed cell death, in cancer cells. This leads to a reduction in tumor size or a slowing of its growth, which is the basis of its use as a chemotherapeutic agent.
The drug’s action is not exclusive to cancer cells, as it also affects healthy, rapidly dividing cells. These include cells in the bone marrow, the gastrointestinal tract lining, and hair follicles. This impact on healthy tissues causes many of the common side effects associated with methotrexate therapy.
Anti-Inflammatory and Immunosuppressive Effects
When used in lower doses for autoimmune diseases like rheumatoid arthritis, methotrexate’s mechanism is more complex and not focused on stopping cell division. One action is the promotion of adenosine release at sites of inflammation. Adenosine has potent anti-inflammatory properties, and by inhibiting enzymes that break it down, methotrexate causes it to accumulate and suppress the inflammatory response.
Another mechanism involves its direct effects on the immune system, where it can induce apoptosis in activated T-lymphocytes. In autoimmune disorders, these T-cells drive the inflammatory process and attack the body’s own tissues. Reducing the number of these activated immune cells helps to dampen the aberrant immune response.
The drug also inhibits the enzyme AICAR transformylase. This inhibition leads to the intracellular buildup of a molecule called AICAR, which contributes to the increase in adenosine levels. These combined actions on adenosine signaling and immune cells result in the drug’s immunosuppressive and anti-inflammatory effects.
The Role of Folic Acid Supplementation
Patients receiving methotrexate are often prescribed a folic acid or folinic acid supplement to manage side effects. Because methotrexate blocks folate, it can negatively impact healthy cells that require this vitamin, not just the targeted disease cells. This can lead to issues like mouth sores, nausea, and decreased blood cell counts due to its effect on bone marrow.
A folic acid supplement provides the body with enough folate to help protect these healthy cells and minimize adverse effects. The supplement offers a rescue pathway for non-cancerous cells in the digestive tract and bone marrow, allowing them to continue their necessary functions.
The timing and dosage of the folic acid supplement are managed by a physician. The goal is to provide protective benefits for healthy tissues without interfering with the therapeutic effectiveness of methotrexate on the targeted cancer or immune cells.