antimetabolite

**Definition/Mechanism:** Antimetabolites are structural analogs of normal metabolites (folate, purines, pyrimidines) that compete for or inhibit enzymes needed for nucleotide synthesis, or are incorporated into DNA/RNA and cause chain termination or dysfunction. Cell-cycle specific: **S phase** (hydroxyurea also S phase; note that methotrexate is S-phase specific as well).

**Major agents (high-yield):** - **Methotrexate (MTX)** – Folate analog; inhibits **dihydrofolate reductase (DHFR)** → decreased dTMP → decreased DNA synthesis. Uses: ALL, lymphoma, choriocarcinoma, breast cancer, osteosarcoma (high dose), RA, psoriasis, ectopic pregnancy, medical abortion (with misoprostol), Crohn disease. Toxicity: myelosuppression (reversible with **leucovorin/folinic acid rescue**), mucositis, hepatotoxicity (fibrosis/cirrhosis), pulmonary fibrosis, nephrotoxicity (crystal precipitation), teratogenic. Avoid with TMP-SMX and NSAIDs/PPIs/penicillins (decreased renal clearance). - **5-Fluorouracil (5-FU) / capecitabine** – Pyrimidine analog; its metabolite FdUMP irreversibly inhibits **thymidylate synthase** (requires reduced folate cofactor; leucovorin potentiates the effect). Uses: colon cancer, pancreatic cancer, actinic keratosis (topical), basal cell carcinoma. Toxicity: myelosuppression, mucositis, hand-foot syndrome (capecitabine), **DPD deficiency** → severe toxicity. Thymidine rescue can be used for 5-FU toxicity (uridine triacetate is the antidote for overdose). - **6-Mercaptopurine (6-MP) / azathioprine** – Purine analogs; inhibit de novo purine synthesis. Activated by HGPRT; inactivated by **xanthine oxidase** (and TPMT). Toxicity increased with **allopurinol/febuxostat** (reduce dose by ~75%) and **TPMT deficiency**. Uses: ALL, IBD, immunosuppression (transplant, autoimmune disease). Toxicities: myelosuppression, hepatotoxicity, GI. - **Cladribine, fludarabine** – Purine analogs; used for hairy cell leukemia (cladribine), CLL (fludarabine). Toxicity: myelosuppression, opportunistic infections, neurotoxicity. - **Cytarabine (Ara-C)** – Pyrimidine analog; inhibits DNA polymerase. Use: AML. Toxicity: myelosuppression (pancytopenia), cerebellar toxicity at high dose, megaloblastic anemia. - **Gemcitabine** – Pyrimidine analog; inhibits ribonucleotide reductase. Used for pancreatic cancer. - **Hydroxyurea** – Inhibits ribonucleotide reductase (decreases dNTPs). Uses: CML, sickle cell disease (increases HbF), polycythemia vera, essential thrombocythemia. - **Mycophenolate** – IMPDH inhibitor (guanine nucleotide synthesis); immunosuppressant, antimetabolite class in transplant. - **Leflunomide** – Inhibits dihydroorotate dehydrogenase (pyrimidine synthesis); RA.

**Common toxicities:** Bone marrow suppression, GI mucositis, alopecia — due to effects on rapidly dividing cells. Many are teratogenic.

**Clinical pearls:** - Megaloblastic anemia from MTX/hydroxyurea/5-FU resembles folate/B12 deficiency (macrocytosis with hypersegmented neutrophils may be absent in drug effect; the key is impaired DNA synthesis). - Leucovorin (folinic acid) bypasses DHFR block → rescues normal cells from MTX; does the opposite (enhances) for 5-FU. - Check TPMT before 6-MP/azathioprine; check DPD before 5-FU/capecitabine. - Tumor lysis syndrome may occur with effective therapy of high-turnover malignancies.