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Mitotic Inhibitors

By

Lisa G. Barber

, DVM, DACVIM, Cummings School of Veterinary Medicine, Tufts University;


Kristine E. Burgess

, DVM, DACVIM (Oncology), Cummings School of Veterinary Medicine, Tufts University

Last full review/revision Nov 2015 | Content last modified Nov 2015

Vinca Alkaloids:

The vinca alkaloids are large, complex molecules derived from the periwinkle plant. Binding to tubulin, the major component of cellular microtubules, accounts for the antineoplastic effects of these drugs. Vinca alkaloids inhibit microtubule polymerization and increase microtubule disassembly. The mitotic spindle apparatus is disrupted, and segregation of chromosomes in metaphase is arrested. These effects account for the primary M-phase action of vinca alkaloids, although other antitubulin effects related to cytoskeletal maintenance and protein trafficking may be seen. The two drugs of importance in this class are vincristine and vinblastine. Both are given IV, and both cause severe local vesication if injected perivascularly. Drug extravasation may cause severe tissue reactions and promote exacerbation of self-trauma. The vinca alkaloids are metabolized primarily in the liver but may be partially excreted in an unchanged form in the urine. Although vinca alkaloids are related structurally, resistance to one does not imply resistance to all drugs in this category. Vincristine use is limited by neurologic toxicity that may include a slowly reversible sensorimotor peripheral neuropathy and muscle weakness. In comparison, the dose-limiting toxicity associated with vinblastine is related to myelosuppression and leukopenia; neurologic toxicity develops only at high doses.

Vinorelbine is a second-generation semisynthetic vinca alkaloid that is derived from vinblastine but with broader antitumor efficacy. According to studies in the veterinary literature, this drug may have efficacy in canine primary lung and cutaneous mast cell tumors.

Taxanes:

Paclitaxel and docetaxel are antimicrotubule agents extracted from the Pacific and European yew trees, respectively. Taxanes bind to tubulin subunits, enhance microtubule polymerization, and inhibit microtubule depolymerization. Formation of stable microtubule bundles disrupts tubulin equilibrium and blocks normal progression through metaphase, and mitosis is arrested. These agents are actively used in human medicine, but hypersensitivity reactions related to the vehicle (polyethoxylated castor oil) have limited the drug's utility in veterinary medicine. A new water-soluble, micellar formulation of paclitaxel has received conditional approval by the FDA for treatment of canine mammary carcinoma and squamous cell carcinoma. Myelosuppression and GI effects (diarrhea, mucosal ulceration, and emesis) have been reported in dogs treated with paclitaxel.

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