microtubule inhibitor

**Background:** Microtubules are polymers of α- and β-tubulin dimers. They form the mitotic spindle, and they also support axonal transport, intracellular vesicle/organelle movement, cilia/flagella, and cell shape. Dynamic instability (cycles of polymerization and depolymerization) is required for chromosome segregation. Drugs that interfere with it arrest cells in M phase (metaphase-to-anaphase transition, via the spindle assembly checkpoint) and cause apoptosis. These drugs are cell-cycle specific (M phase).

**Anticancer classes** - **Vinca alkaloids** (vincristine, vinblastine, vinorelbine) - Mechanism: bind β-tubulin and **block polymerization** (they prevent microtubule assembly), so the mitotic spindle cannot form. - Mnemonic: "Vinca alkaloids **v**ery **in**hibit **c**ell **a**ssembly" / "Vin-blast the spindle." - Vincristine: **peripheral neuropathy** (stocking-glove paresthesias, foot drop, areflexia), **constipation/paralytic ileus**, SIADH, and **minimal myelosuppression** ("vinCRIStine = CRISp nerves"). Used for ALL (especially childhood), Hodgkin (MOPP/BEACOPP), non-Hodgkin lymphoma (R-CHOP), Wilms tumor, neuroblastoma, and rhabdomyosarcoma. - Vinblastine: **myelosuppression** ("vinBLASTine BLASTs the marrow"). Used for Hodgkin (ABVD), testicular cancer, Kaposi sarcoma, and histiocytosis. - Vinorelbine: used in non-small cell lung cancer (NSCLC). - **Taxanes** (paclitaxel, docetaxel, cabazitaxel; also nab-paclitaxel) - Mechanism: bind β-tubulin and **hyperstabilize** polymerized microtubules, which prevents depolymerization. The result is a nonfunctional spindle and mitotic arrest. - Mnemonic: "**Tax**anes **tax**ing the cell's ability to disassemble." - Toxicities: myelosuppression (especially neutropenia), **peripheral neuropathy**, **hypersensitivity reactions** (Cremophor vehicle; premedicate with corticosteroids and antihistamines), alopecia, and fluid retention (docetaxel). - Uses: breast, ovarian, lung, prostate, and Kaposi sarcoma. Paclitaxel is also used on drug-eluting coronary stents. - **Eribulin** (breast cancer) inhibits microtubule growth. **Antibody-drug conjugates** carry microtubule toxins: brentuximab vedotin (MMAE; CD30), trastuzumab emtansine (DM1; HER2). Brentuximab can cause PML and peripheral neuropathy.

**Non-oncologic microtubule inhibitors** - **Griseofulvin:** interferes with fungal microtubules and mitotic spindle function. It is deposited in keratin-containing tissues and is used for dermatophytes (tinea capitis, ungual infections). Toxicities: teratogenicity, hepatotoxicity, CYP450 inducer, disulfiram-like reaction, and warfarin interaction. - **Mebendazole/albendazole (benzimidazoles):** bind helminth β-tubulin and impair microtubule synthesis and glucose uptake. Used for nematodes (e.g., pinworm, roundworm, hookworm). Albendazole is also used for neurocysticercosis and hydatid disease. Teratogenic. - **Colchicine:** binds tubulin, impairs microtubule polymerization, and blocks neutrophil chemotaxis and degranulation. Used for acute gout and FMF. Toxicity: GI upset (diarrhea), and bone marrow suppression and myopathy in overdose.

**Resistance:** Resistance arises from P-glycoprotein (MDR1) efflux pumps and from tubulin mutations or altered isotype expression.

**Exam pearls** - Cell-cycle specificity: microtubule inhibitors = M phase. Antimetabolites = S phase. Bleomycin = G2. Etoposide/topoisomerase inhibitors = S/G2. - Vincristine: neuropathy and constipation, with little marrow suppression. Vinblastine: marrow suppression. - Taxanes stabilize. Vincas destabilize (block assembly). Both cause mitotic arrest. - Peripheral neuropathy is common to both classes because of impaired axonal transport.