Chlorambucil

Chlorambucil belongs to the class of alkylating agents (nitrogen mustards) and has both cytotoxic and immunosuppressive effects.

CHEMICAL STRUCTURE AND PHARMACOKINETIC PROPERTIES

Following oral administration, chlorambucil is rapidly absorbed from the gastrointestinal tract by passive diffusion, particularly if the patient is fasting. It is metabolised by the microsomal system in the liver. The urinary excretion of inactive metabolites is low and lasts, on average, 24 hours. The concomitant administration of glucocorticoids potentiates the cytotoxic effect of chlorambucil (synergistic effect).

MECHANISM OF ACTION

Chlorambucil is a bifunctional alkylating agent whose action is not dependent on a specific phase of the cell cycle. Its cytotoxic effect is due to the transfer of two active chloroethylene groups to DNA molecules (position N_⁷of guanine). The formation of cross-links between the DNA chains underlies the cytotoxicity; these bonds prevent the separation of the chains of nucleic acids, inhibiting cell division and/or causing complete breakage of the DNA. Chlorambucil also inhibits the synthesis of RNA and intracellular proteins.

MECHANISM OF RESISTANCE

Malignant cells become resistant to chlorambucil following repair of the damaged DNA through removal of the alkylated nucleotides.

CLINICAL INDICATIONS AND DOSE

Chlorambucil is active against both rapidly proliferating cells and resting ones, a reason why it is the drug of choice for the treatment of chronic lymphocytic leukaemia. Other indications include lymphomas (instead of cyclophosphamide), multiple myeloma, polycythemia vera and mast cell tumours.

Chlorambucil is administered at a dose of 0.2 mg/kg/die per os (continuous treatment) or 2-6 mg/m_²/die per os. In a pulsed regimen, it is given at a dose of 8 mg/m_²/die per os for 5 days.

TOXICITY

Chlorambucil-induced toxicity affects the following organs and systems:

• bone marrow: dose-limiting and cumulative myelosuppression (particularly neutropenia), which is more severe in the case of continuous administration than if the drug is given intermittently or in a pulsatile manner.
• gastrointestinal tract: generally mild. Can be more severe in the case of unfractionated doses. Nausea, loss of appetite.
• nervous system: rare and reversible neurological toxicity, characterized by fasciculation, tremors and epileptic crises. Chlorambucil must not be administered to animals with a history of neuropathy or to those being treated with anti-epileptic drugs. Neurological toxicity is common in the case of overdose.

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. Miller E: The use of cytotoxic agents in the treatment of immune-mediated diseases of dogs and cats. Semin Vet Med Surg (Small Anim). 12: 157, 1997.
3. Marconato L: Agenti alchilanti. In: Principi di chemioterapia in oncologia, Marconato (ed), Poletto Editore, 2009: 93-113.
4. Taylor F, Gear R, Hoather T, Dobson J: Chlorambucil and prednisolone chemotherapy for dogs with inoperable mast cell tumours: 21 cases. J Small Anim Pract. 50: 284, 2009.