Explain why folic acid is given with methotrexate.
Methotrexate (MTX) is a folate antagonist widely used in chemotherapy and for autoimmune diseases such as rheumatoid arthritis and psoriasis. Its therapeutic effect arises from inhibition of dihydrofolate reductase (DHFR), which converts dihydrofolate to tetrahydrofolate (THF). THF is essential for synthesizing purines and pyrimidines, the building blocks of DNA. By blocking DHFR, MTX deprives rapidly dividing cells, including cancer cells and activated immune cells, of necessary folate derivatives, thereby inhibiting DNA synthesis and cell proliferation.
However, healthy rapidly dividing cells in the bone marrow and gastrointestinal tract are also affected, causing myelosuppression, mucositis, and gastrointestinal distress. To reduce toxicity, folic acid or leucovorin (folinic acid) is administered concurrently in a strategy called folate rescue. This allows normal cells to bypass DHFR inhibition, maintain essential DNA synthesis, and reduce side effects, while target cells remain sensitive to folate depletion, preserving anti-cancer and immunosuppressive efficacy.
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