Updated: 8/7/2020

Antimetabolites

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Topic
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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Questions (6)
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