antimetabolites

Antimetabolites act as false substrates or enzyme inhibitors in nucleotide synthesis pathways, disrupting DNA/RNA replication and are cell-cycle specific (S phase). Key mechanisms: (1) Methotrexate - inhibits dihydrofolate reductase (DHFR), blocking conversion of dihydrofolate to tetrahydrofolate, needed for purine/thymidine synthesis; used in cancers (leukemia, lymphoma, choriocarcinoma), rheumatoid arthritis, psoriasis, and ectopic pregnancy; toxicity includes myelosuppression (reversible with leucovorin rescue), hepatotoxicity, mucositis, pulmonary fibrosis. (2) 5-Fluorouracil (5-FU) - pyrimidine analog converted to 5F-dUMP, which inhibits thymidylate synthase, decreasing dTMP and DNA synthesis; used in colorectal, pancreatic, and skin cancers (topical for actinic keratosis/BCC); toxicity includes myelosuppression, mucositis, photosensitivity; not reversed by leucovorin rescue (enhances toxicity actually via ternary complex stabilization used therapeutically). (3) 6-Mercaptopurine (6-MP)/Azathioprine - purine analogs activated by HGPRT, inhibit de novo purine synthesis; metabolized by xanthine oxidase—toxicity increased with allopurinol; used in leukemia (ALL) and as immunosuppressants (organ transplant, IBD, autoimmune disease); toxicity includes myelosuppression, hepatotoxicity. (4) Cytarabine (ara-C) - pyrimidine analog inhibiting DNA polymerase; used in AML, lymphomas; toxicity includes pancytopenia, megaloblastic anemia. (5) Hydroxyurea - inhibits ribonucleotide reductase, blocking DNA synthesis (S phase specific); used in CML, sickle cell disease (increases HbF), and polycythemia vera; toxicity includes severe myelosuppression, GI upset. Clinical correlations: antimetabolites are foundational in combination chemotherapy regimens and immunosuppressive therapy; understanding their mechanisms is essential for predicting drug interactions (e.g., allopurinol + azathioprine) and adverse effects tested on boards.