Foundations · Year 1 · from Foundations
Case 3: Methotrexate Toxicity (Antifolate Therapy)
Clinical Image
Source: Wikipedia - Mucositis - CC BY-SA 3.0
Case Presentation
A 62-year-old woman receiving high-dose methotrexate for osteosarcoma develops severe mucositis, diarrhea, and pancytopenia one week after her chemotherapy cycle. She was supposed to receive leucovorin rescue starting 24 hours after methotrexate but missed several doses due to nausea. Physical examination reveals oral ulcerations with white plaques, diffuse abdominal tenderness, and pallor. Laboratory studies show WBC 1,200/mm3, hemoglobin 8.5 g/dL, platelets 45,000/mm3, and elevated creatinine at 2.1 mg/dL. Serum methotrexate level is elevated at 0.8 micromolar (should be <0.1 at this timepoint). She has methotrexate toxicity exacerbated by renal impairment. Methotrexate inhibits dihydrofolate reductase (DHFR), blocking regeneration of tetrahydrofolate (THF) required for one-carbon transfers in purine and thymidylate synthesis. Without THF, cells cannot synthesize DNA, particularly affecting rapidly dividing cells (bone marrow, GI mucosa). She is treated with high-dose leucovorin (folinic acid, which bypasses DHFR), IV fluids for hydration, and urinary alkalinization to enhance methotrexate excretion. Her counts recover over the following week.
Key Learning Points
- Methotrexate inhibits dihydrofolate reductase (DHFR), preventing regeneration of tetrahydrofolate required for de novo synthesis of purines (N10-formyl-THF) and thymidylate (N5,N10-methylene-THF)
- Rapidly dividing cells are most sensitive to folate antagonists; toxicity manifests as mucositis (GI epithelium) and myelosuppression (bone marrow)
- Leucovorin (folinic acid) rescue provides reduced folate that bypasses DHFR; timing and adequate dosing are critical, especially when methotrexate clearance is impaired by renal dysfunction