Antimetabolites

Overview

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)

Cytarabine (ara-C)