Vincristine

Vincristine is a vinca alkaloid derived from the periwinkle plant (Vinca minor). Vincristine is extensively used in veterinary oncology, as both monotherapy and in polychemotherapy. The drug is also used in the treatment of immune-mediated thrombocytopenia.

CHEMICAL STRUCTURE AND PHARMACOKINETIC PROPERTIES

Vincristine is composed of a vindoline ring linked to a catharanthine ring by means of carbon-carbon bonds. A formyl group is attached to the vindoline ring.

The pharmacokinetic properties of vincristine are consistent with a three-compartment model: extensive distribution in extravasal compartments, a high clearance rate and a long terminal half-life (with a consequent prolonged elimination).

Following intravenous administration 90% of vincristine is distributed in tissues and binds strongly, but reversibly to the tissues. In the dog vincristine accumulates, especially within the spleen.

Up to 40-50% of the administered dose binds to plasma proteins, red blood cells and platelets. Vincristine does not cross the blood-brain barrier. It is metabolised in the liver by cytochrome P-450.

Vincristine is then eliminated preferentially (70%) in the faeces (for 7 days), partially in the form of active compound. About 10% is excreted in the urine (for 4 days), with 50% of the product excreted by this route being eliminated in a non-modified form. Vincristine is no longer detectable in the serum 7 days after administration.

MECHANISM OF ACTION

Tubulin is a structural protein that polymerises to form microtubules, which make up the cytoskeleton and the mitotic spindle. Vincristine binds to tubulin, preventing the assembly of microtubules and, consequently,  the formation of the mitotic spindle. This inhibits the separation of  chromosomes which have duplicated and cell division does not take place: the cells are blocked in metaphase. Vincristine is, therefore, both a phase-specific agent, which acts during the M phase (mitosis) of the cell cycle, and an antimicrotubular agent.

MECHANISM OF RESISTANCE

Resistance to vincristine is caused by the expression of glycoprotein P-170, which leads to the extrusion of the chemotherapeutic agent from the neoplastic cell, and by modification of the target, i.e., tubulin.

CLINICAL INDICATIONS AND DOSE

Used in combination with other drugs vincristine is indicated for the treatment of high grade lymphomas and acute leukaemias, carcinomas and sarcomas.  As a single agent it is used in the treatment of transmissible venereal tumours.

In the dog the dose is 0.5-0.75 mg/m_² by rapid intravenous bolus injection every 1-3 weeks. In the cat the dose is 0.03 mg/kg by rapid intravenous bolus injection.

TOXICITY

The adverse events of vincristine involve various organs and apparatuses:

• bone marrow: mild, non-cumulative myelosuppression.  It can cause an increase in platelet count as a result of endo-reduplication of megakaryocytes. When administered together with L-asparaginase [6], vincristine should be given 12-24 hours before the enzyme. If L-asparaginase is administered together or before vincristine it may reduce the clearance of this latter, thus causing severe neutropenia. Bone marrow toxicity is severe in dogs with a recessive or dominant mutation of ABCB1-1D, the gene which codes for glycoprotein P, because in such cases vincristine is not eliminated efficiently from the body;
• skin: vincristine causes blistering. Accidental perivascular extravasation causes inflammation, ulcerations and even tissue necrosis (Figs. 1 and 2). In the case of extravasation the injection must be stopped immediately and the remaining dose injected into another vein.  A local infiltration with hyaluronidase (an enzyme that breaks down hyaluronic acid) and the application of hot packs for 20 minutes, 4-6 times a day, may facilitate the dispersion of the drug, minimise the irritation and reduce the risk of necrosis;
• nervous system: usually symmetrical peripheral paraesthesia, loss of sensitivity, loss of motor function with muscle weakness. The neurotoxicity is dose-dependent and reversible;
• gastrointestinal apparatus: mild. In the cat vincristine may cause paralytic ileus and constipation.

  Fig. 1                                       Fig. 2

Suggested readings

1. Chun R, Garrett LD, Vail DM: Cancer chemotherapy. In: Withrow & MacEwen’s Small Animal Clinical Oncology, Withrow SJ and Vail DM (eds), Saunders Elevier, 2007: 163-192.
2. Gonzalez CM, Griffey SM, Naydan DK et al: Canine transmissible venereal tumour: a morphological and immunohistochemical study of 11 tumours in growth phase and during regression after chemotherapy. J Comp Pathol. 2000; 122: 241-8.
3. Hamilton TA, Cook JR Jr, Braund KG et al: Vincristine-induced peripheral neuropathy in a dog. J Am Vet Med Assoc. 1991; 198: 635-8.
4. Harrison SD Jr: An investigation of the mouse as a model for vincristine toxicity. Cancer Chemother Pharmacol. 1983; 11: 62-5.
5. Knobloch A, Mohring SA, Eberle N, et al: Drug residues in serum of dogs receiving anticancer chemotherapy. J Vet Intern Med. 2010; 24: 379-83.
6. Knobloch A, Mohring SA, Eberle N, et al: Cytotoxic drug residues in urine of dogs receiving anticancer chemotherapy. J Vet Intern Med. 2010; 24: 384-90.
7. Marconato L: Agenti alchilanti. In: Principi di chemioterapia in oncologia, Marconato (ed), Poletto Editore, 2009: 79-92.
8. Mealey KL, Northrup NC, Bentjen SA: Increased toxicity of P-glycoprotein-substrate chemotherapeutic agents in a dog with the MDR1 deletion mutation associated with ivermectin sensitivity. J Am Vet Med Assoc. 2003; 223: 1453-5.
9. Northrup NC, Rassnick KM, Snyder LA et al: Neutropenia associated with vincristine and L-asparaginase induction chemotherapy for canine lymphoma. J Vet Intern Med. 2002; 16: 570-5.
10. Rozanski EA, Callan MB, Hughes D et al: Comparison of platelet count recovery with use of vincristine and prednisone or prednisone alone for treatment for severe immune-mediated thrombocytopenia in dogs. J Am Vet Med Assoc. 2002; 220: 477-81.