Antimetabolites, Microtubule & Topoisomerase Inhibitors
What each drug blocks, when in the cycle it strikes, and what rescues the patient
Cell-cycle specificity
Why phase matters. These drugs kill only cells that are actively cycling, each at a characteristic phase. A single exposure kills only the fraction of cells passing through the vulnerable phase, so the drugs are schedule-dependent (prolonged infusions, repeated doses) and work best against tumors with a high growth fraction, such as leukemias, lymphomas and germ cell tumors. Alkylators and platinums, covered separately, are cycle-nonspecific and also kill resting (G0) cells.
- G0/G1Resting or growing cells: only cycle-nonspecific drugs such as alkylators, platinums and anthracyclines reliably kill
- S phaseAll antimetabolites; topoisomerase I inhibitors (irinotecan, topotecan)
- G2Etoposide (late S–G2); bleomycin
- M phaseVinca alkaloids block microtubule assembly; taxanes block disassembly
Antifolates: methotrexate and pemetrexed
Mechanism. Methotrexate inhibits dihydrofolate reductase (DHFR). Thymidylate synthase methylates dUMP to dTMP using 5,10-methylene-THF and leaves dihydrofolate behind, so without DHFR the reduced-folate pool empties: dTMP and de novo purine synthesis stop and cells die in S phase ("thymineless death"). Polyglutamation traps the drug inside cells. At low weekly doses for rheumatoid arthritis, much of the benefit comes from adenosine release through AICAR transformylase inhibition rather than cell killing.
Uses. ALL, choriocarcinoma, osteosarcoma (high dose), primary CNS lymphoma and breast cancer; first-line DMARD for rheumatoid arthritis; psoriasis, Crohn disease and unruptured ectopic pregnancy.
Toxicity and interactions. Mucositis and myelosuppression appear acutely; hepatic fibrosis or cirrhosis and a hypersensitivity pneumonitis (which can progress to pulmonary fibrosis) appear with chronic use; the drug is teratogenic and abortifacient. At high doses it precipitates in acidic urine and causes crystal nephropathy. Because it is excreted by the kidney, NSAIDs, proton pump inhibitors, penicillins and probenecid slow its clearance, and trimethoprim-sulfamethoxazole both slows clearance and adds a second antifolate effect, a classic trigger of pancytopenia.
Low-dose methotrexate is taken once weekly; accidental daily dosing causes fatal marrow and mucosal toxicity.
- PrepareIV hydration and urine alkalinization (pH ≥7); withhold interacting drugs
- Leucovorin rescueFolinic acid (5-formyl-THF) enters the folate pool beyond the DHFR block, sparing marrow and mucosa
- MonitorPlasma methotrexate levels and creatinine decide how long rescue continues
- Clearance failsGlucarpidase (carboxypeptidase G2) cleaves circulating methotrexate to inactive metabolites
Folic acid cannot rescue methotrexate toxicity because it must itself be reduced by DHFR; leucovorin is already reduced.
Pemetrexed. A multitargeted antifolate (thymidylate synthase, DHFR and GAR transformylase) used for nonsquamous non-small cell lung cancer and mesothelioma. Oral folic acid plus intramuscular vitamin B12, begun before the first dose, lowers the risk of severe myelosuppression and mucositis; dexamethasone prevents its rash.
Pyrimidine analogs, purine analogs and hydroxyurea
| Drug | Mechanism | Main uses | Signature toxicity |
|---|---|---|---|
| 5-Fluorouracil; capecitabine (oral prodrug) | 5-FdUMP traps thymidylate synthase with methylene-THF; FUTP enters RNA | Colorectal (FOLFOX, FOLFIRI) and other GI cancers, breast, head and neck; topical for actinic keratosis | Myelosuppression, mucositis, diarrhea, hand-foot syndrome, coronary vasospasm |
| Cytarabine (ara-C) | Ara-CTP inhibits DNA polymerase and terminates chains | AML induction (7+3) and high-dose consolidation | Myelosuppression; cerebellar syndrome and conjunctivitis at high dose |
| Gemcitabine | Deoxycytidine analog; inhibits ribonucleotide reductase and enters DNA | Pancreatic, lung, bladder, biliary, ovarian cancer | Myelosuppression (thrombocytopenia), flu-like illness, pneumonitis |
| 6-Mercaptopurine; azathioprine (prodrug) | HGPRT converts to thioguanine nucleotides; blocks purine synthesis | ALL maintenance; transplant, IBD, autoimmune disease | Myelosuppression (TPMT/NUDT15), hepatotoxicity, pancreatitis |
| Cladribine | Adenosine deaminase–resistant purine analog; kills resting lymphocytes | Hairy cell leukemia | Myelosuppression, prolonged lymphopenia |
| Fludarabine | Purine analog; inhibits DNA synthesis | CLL; transplant and CAR-T conditioning | CD4 lymphopenia with opportunistic infections, autoimmune hemolytic anemia |
| Hydroxyurea | Inhibits ribonucleotide reductase → ↓dNTPs | Sickle cell disease (↑HbF); PV, ET, CML cytoreduction | Myelosuppression, macrocytosis, teratogenicity |
5-FU and leucovorin. Leucovorin enlarges the methylene-THF pool and stabilizes the inhibitory ternary complex, so with 5-FU it potentiates rather than rescues. Capecitabine is converted to 5-FU in tissues, the last step by thymidine phosphorylase, which is abundant in tumors. Dihydropyrimidine dehydrogenase (DPD, gene DPYD) catabolizes more than 80% of a 5-FU dose; DPD-deficient patients develop catastrophic mucositis, diarrhea, neutropenia and neurotoxicity, and pretreatment DPYD genotyping can identify them. Uridine triacetate is the antidote for overdose or early severe toxicity.
Cytarabine. "7+3" means 7 days of continuous cytarabine plus 3 days of an anthracycline (daunorubicin or idarubicin). High-dose cytarabine causes ataxia, nystagmus and dysarthria, more often with renal impairment and older age, so neurologic checks precede every dose; corticosteroid eye drops prevent the chemical conjunctivitis. Unlike vincristine, cytarabine and methotrexate can be given intrathecally.
Thiopurines are inactivated by thiopurine methyltransferase (TPMT) and xanthine oxidase. TPMT or NUDT15 deficiency causes life-threatening myelosuppression, so test before dosing; with allopurinol or febuxostat, cut the dose to about 25–33% or avoid the combination.
Lymphotoxic purine analogs. Cladribine accumulates in lymphocytes, which are rich in deoxycytidine kinase, and one course gives durable remission of hairy cell leukemia. Fludarabine's prolonged CD4 lymphopenia predisposes to Pneumocystis and herpesvirus infections, and patients receive irradiated blood to prevent transfusion-associated graft-versus-host disease.
Hydroxyurea in sickle cell disease. Raising HbF reduces pain crises, acute chest syndrome and transfusion needs. Macrocytosis is expected, so a rising MCV doubles as an adherence check; skin and nail hyperpigmentation and leg ulcers also occur.
Microtubule and topoisomerase inhibitors
| Drug | Mechanism (phase) | Dose-limiting or signature toxicity | Classic uses |
|---|---|---|---|
| Vincristine | Binds β-tubulin, blocks polymerization (M) | Peripheral and autonomic neuropathy, ileus, SIADH; little marrow toxicity | ALL, lymphomas, Wilms tumor, rhabdomyosarcoma |
| Vinblastine | Blocks polymerization (M) | Myelosuppression | Hodgkin lymphoma (ABVD), Kaposi sarcoma |
| Paclitaxel | Stabilizes polymerized microtubules (M) | Neuropathy, neutropenia, infusion hypersensitivity, alopecia | Breast, ovarian, lung cancer |
| Docetaxel | Stabilizes microtubules (M) | Neutropenia, fluid retention, nail changes | Breast, prostate, lung cancer |
| Irinotecan | Traps topoisomerase I (S) | Early cholinergic and late diarrhea, neutropenia | Colorectal (FOLFIRI), pancreatic cancer |
| Topotecan | Traps topoisomerase I (S) | Myelosuppression | Ovarian cancer, small cell lung cancer |
| Etoposide | Traps topoisomerase II (late S–G2) | Myelosuppression, alopecia, hypotension if infused fast; t-AML | Testicular cancer (BEP), small cell lung cancer |
Vinca alkaloids. Vincristine and vinblastine bind β-tubulin and prevent polymerization, arresting cells in metaphase. Vincristine's neuropathy is dose-limiting: paresthesias, loss of ankle reflexes and foot drop, plus autonomic constipation that can progress to paralytic ileus.
Vincristine is fatal if given intrathecally (ascending paralysis); it is supplied for intravenous use only.
Taxanes. Paclitaxel and docetaxel bind β-tubulin and hyperstabilize microtubules so the spindle cannot disassemble. Paclitaxel's solvent causes infusion hypersensitivity, prevented by dexamethasone plus H1 and H2 blockers; albumin-bound (nab-) paclitaxel avoids the castor-oil solvent and needs no such premedication. The sensory neuropathy has a stocking-glove distribution.
Topoisomerase I inhibitors. Irinotecan and topotecan trap topoisomerase I on nicked DNA; when replication forks collide with the trapped complex, single-strand breaks become lethal double-strand breaks. Irinotecan is a prodrug whose active metabolite SN-38 is inactivated by UGT1A1 glucuronidation, so UGT1A1*28 homozygotes (the Gilbert syndrome genotype) accumulate SN-38 and develop severe neutropenia and diarrhea. Early diarrhea is cholinergic and responds to atropine; late diarrhea needs aggressive high-dose loperamide.
Etoposide and secondary leukemia. Etoposide stabilizes the topoisomerase II–DNA cleavage complex, leaving double-strand breaks. Therapy-related AML after topoisomerase II inhibitors appears 1–3 years after exposure, without a myelodysplastic phase, and carries balanced KMT2A (11q23) rearrangements. Alkylator-related t-AML appears after 5–10 years, follows MDS and shows loss of chromosome 5 or 7 material.
Rescue agents and supportive measures
- Leucovorin: rescues normal cells after methotrexate; potentiates 5-FU.
- Glucarpidase: clears methotrexate when renal excretion fails; hydration and urine alkalinization help prevent that failure.
- Uridine triacetate: 5-FU or capecitabine overdose or early severe toxicity.
- Premedication and prevention: folic acid and vitamin B12 for pemetrexed; dexamethasone plus H1 and H2 blockers for paclitaxel (dexamethasone also limits docetaxel fluid retention); corticosteroid eye drops for high-dose cytarabine.
- Atropine, then high-dose loperamide: early and late irinotecan diarrhea.
- Genotype-guided dosing: TPMT/NUDT15 (thiopurines), DPYD (fluoropyrimidines), UGT1A1 (irinotecan).