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Updated: Aug 7 2020

Antimetabolites

  • Overview
    • All are S-phase specific
  • Methotrexate
    • Mechanism
      • inhibits folate metabolism
        • folic acid analog
        • inhibits dihydrofolate reductase
        • ↓ dTMP → ↓ DNA and ↓ protein synthesis
    • Clinical use
      • cancer
        • leukemias
        • lymphomas (except Hodgkin lymphoma)
        • breast cancer
        • choriocarcinoma
        • sarcomas
      • non-cancer
        • rheumatoid arthritis
        • psoriasis
        • abortion
        • ectopic pregnancy
    • Toxicity
      • myelosuppression
        • leucovorin (folinic acid) reverses high-dose methotrexate toxicity
          • known as leucovorin "rescue"
        • monitor neutrophil count
      • fatty change in liver
        • macrovesicular
      • mucositis
        • folate supplementation is indicated for all patients on low-dose chronic methotrexate to reduce risk for toxicity
        • leucovorin can be used in patients who are not responsive to folate supplementation
      • teratogenic
  • 5-Fluorouracil (5-FU)
    • Mechanism
      • pyrimidine analog
        • bioactivated to 5F-dUMP
          • covalently complexes to folic acid
        • complex inhibits thymidylate synthase
      • ↓ dTMP → ↓ DNA and ↓ protein synthesis
      • synergistic with MTX
    • Clinical use
      • colon cancer
      • basal cell carcinoma (topical)
      • breast cancer
      • ovarian cancer
      • head and neck cancer
    • Toxicity
      • myelosuppression
        • "rescue" with thymidine
        • NOT reversible with leucovorin, in fact effects are stronger
      • photosensitivity
  • 6-Mercaptopurine (6-MP)
    • Mechanism
      • purine analog
        • activated by HGPRTase
      • ↓ de novo purine synthesis
    • Clinical use
      • leukemias
        • ALL
        • not CLL
      • lymphomas
        • not Hodgkin's
      • immunosuppression
    • Toxicity
      • myelosuppression
      • GI
      • liver
      • allopurinol increases toxicity
        • 6-MP is metabolized by xanthine oxidase
  • 6-Thioguanine (6-TG)
    • Mechanism
      • same as 6-MP
    • Clinical use
      • ALL
        • can be given with allopurinol
    • Toxicity
      • myelosuppression
      • hepatotoxicity
  • Cytarabine (ara-C)
    • Mechanism
      • pyrimidine analog
        • inhibits DNA polymerase
    • Clinical use
      • AML
      • ALL
      • lymphomas
        • high-grade non-Hodgkin's lymphoma
    • Toxicity
      • leukopenia
      • thrombocytopenia
      • megaloblastic anemia
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