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