Clinical Indications

• Methotrexate is used for treating several neoplastic and autoimmune diseases. As a chemotherapeutic drug, methotrexate is indicated in the treatment of gestational choriocarcinoma, chorioadenoma destruens, hydatidiform mole, acute lymphoblastic leukemia, non-Hodgkin's lymphomas, carcinomas of the breast and ovary, epidermal tumors of the head and neck, small-cell carcinoma of the lung, and non-metastatic osteosarcoma. As an immunosuppressant, it is used for psoriasis, rheumatoid arthritis, juvenile idiopathic arthritis, inflammatory bowel disease, systemic lupus erythematosus, vasculitis, and other connective tissue diseases.
• Methotrexate has distinct mechanisms of action when used in chemotherapy and immunosuppression. In cancer therapy, it acts as an antifolate antimetabolite through competitive inhibition of the enzyme dihydrofolate reductase, determining a reduction of DNA synthesis. In autoimmune diseases, different mechanisms are involved: increase of adenosine, which is an anti-inflammatory compound; modulation of the production of cytokine and adhesion molecules; induction of T cells apoptosis through the formation of reactive oxygen species.
• Since it is a nonspecific cytotoxin, prolongation of methotrexate blood concentrations may lead to severe, unwanted cytotoxic effects (myelosuppression, gastrointestinal mucositis, alopecia, cirrhosis, pulmonary fibrosis, acute kidney injury). To avoid these adverse events, methotrexate therapy is monitored following a methotrexate dose. Toxicity of methotrexate is reversed by leucovorin.
• Administration of high-dose methotrexate followed by Leucovorin rescue treatment showed effectiveness in the treatment of carcinoma of the lung and osteogenic sarcoma.