Anti-Cancer Drugs — Part 1

Two pharmacologically distinct mechanisms are exploited by antimicrotubule drugs. Vinca alkaloids (vincristine, vinblastine, vinorelbine) bind to the beta-tubulin subunit at the vinca domain and, at clinical concentrations, suppress dynamic instability at microtubule plus ends by binding to a small number of tubulin subunits, preventing efficient addition or loss of tubulin dimers. The net effect is kinetic stabilization of the dynamic instability state, generating a mitotic arrest with malformed or absent spindles. At higher concentrations, vinca alkaloids produce complete tubulin depolymerization.

Taxanes (paclitaxel, docetaxel, cabazitaxel) and epothilones bind to the interior of the microtubule lumen at the taxane domain on beta-tubulin, stabilizing the polymer by reducing the off-rate of tubulin subunits and suppressing dynamic instability of the plus end. By locking microtubules in a stabilized, non-dynamic state, taxanes prevent the conformational changes necessary for kinetochore detachment and chromatid separation during anaphase. Both vinca alkaloids and taxanes ultimately trigger apoptosis through sustained activation of the spindle assembly checkpoint, which prevents cell cycle progression and, after a threshold duration of mitotic arrest, triggers caspase-dependent apoptosis. Because this mechanism requires cells to enter and attempt mitosis, antimicrotubule agents are M-phase specific.

Paclitaxel stabilizes microtubules by binding to the beta-tubulin subunit on the interior of the microtubule lumen, promoting tubulin polymerization even in the absence of guanosine triphosphate and inhibiting depolymerization. Because paclitaxel is highly hydrophobic, the original clinical formulation required solubilization in Cremophor EL (polyoxyethylated castor oil), a non-ionic surfactant vehicle that is itself a potent cause of non-immunoglobulin E-mediated hypersensitivity reactions in approximately 10 to 40% of patients without premedication. The Cremophor EL reaction manifests within the first 10 minutes of infusion as flushing, urticaria, bronchospasm, and hypotension — an anaphylactoid reaction that does not require prior sensitization.

Standard premedication with dexamethasone 20 mg orally or intravenously at 12 and 6 hours before infusion, diphenhydramine 50 mg intravenously, and an H2 receptor antagonist (ranitidine or cimetidine) 30 minutes before infusion reduces the incidence of severe hypersensitivity reactions to approximately 1 to 2%. Paclitaxel infusion must use non-polyvinyl chloride tubing because Cremophor EL leaches the plasticizer di(2-ethylhexyl) phthalate from polyvinyl chloride tubing at clinically significant concentrations. Paclitaxel is primarily metabolized by cytochrome P450 2C8, with secondary contributions from cytochrome P450 3A4. The dose-limiting cumulative toxicity is peripheral sensory neuropathy in a stocking-glove distribution, reversible in most patients after treatment completion but incompletely reversible in a significant minority.

Docetaxel shares the beta-tubulin binding site and microtubule stabilization mechanism with paclitaxel but is formulated in polysorbate 80 rather than Cremophor EL, producing a different vehicle-related toxicity: fluid retention (edema, pleural effusions, ascites) that is cumulative and substantially attenuated by pretreatment with dexamethasone 8 mg twice daily for 3 days starting the day before docetaxel. This premedication reduces the incidence and severity of the fluid retention syndrome and also reduces hypersensitivity reactions. The dose-limiting acute toxicity is myelosuppression, more severe than paclitaxel at equivalent doses. Docetaxel also causes nail toxicity (onycholysis, nail discoloration) and a characteristic skin erythema more prominently than paclitaxel. Docetaxel is metabolized predominantly by cytochrome P450 3A4, making interactions with cytochrome P450 3A4 inhibitors and inducers clinically important.

Nab-paclitaxel (albumin-bound paclitaxel) is a 130-nanometer nanoparticle formulation in which paclitaxel is bound noncovalently to human serum albumin, eliminating the need for Cremophor EL. Because Cremophor EL is absent, the standard three-drug hypersensitivity premedication protocol is not required, and non-polyvinyl chloride tubing is not required. Nab-paclitaxel is approved for metastatic breast cancer, non-small cell lung cancer (in combination with carboplatin), and pancreatic adenocarcinoma (in combination with gemcitabine). Despite the absence of Cremophor EL, nab-paclitaxel produces peripheral neuropathy at least as prominent as conventional paclitaxel.

Cabazitaxel is a semisynthetic taxane developed specifically to overcome P-glycoprotein-mediated taxane resistance, as it has low affinity for P-glycoprotein compared to docetaxel and paclitaxel. It is approved for castration-resistant prostate cancer after prior docetaxel-based therapy. The dose-limiting toxicity is myelosuppression, with febrile neutropenia at a rate substantially higher than docetaxel; primary granulocyte colony-stimulating factor prophylaxis is recommended for all patients. Ixabepilone is a semisynthetic analog of epothilone B that binds to the same beta-tubulin site as taxanes, retains activity against tumor cells with P-glycoprotein overexpression and tubulin structural changes that confer taxane resistance, and is approved for metastatic breast cancer after failure of anthracycline and taxane therapy. Ixabepilone is formulated in Cremophor EL and requires the same three-drug premedication protocol as conventional paclitaxel.