58Â° Congresso Nazionale SCIVAC: Oncologia veterinaria

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58° Congresso Nazionale SCIVAC • Milano, 7-9 Marzo 2008 • Oncologia veterinaria - Alle soglie del III Millennio are dependent on DNA/cellular proliferation but are not cell cycle specific. Toxicity is usually expressed when the cell enters the S-phase and is unable to replicate. Pharmacokinetics Cyclophosphamide can be administered orally (PO) or intravenously (IV). The oral administration route shows variable bioavailability ranging from 74- 97%. Following IV administration maximal plasma concentration is achieved in 2-3 hours. Cyclophosphamide is widely distributed into body tissues. In veterinary medicine the recommended dosage for cyclophosphamide is 50 mg/m 2 PO four days per week or a single dose of 250 mg/ m 2 every 3 weeks. Injectable cyclophosphamide is administered at doses ranging from 100-300 mg/m 2 IV as often as once weekly, depending on the protocol involved. Cyclophosphamide is a prodrug that is activated by cytochrome p450 enzymes in the liver. The active 4-hydroxycyclophosphamide is rapidly metabolized to inactive 4-ketocyclophosphamide and carboxyphosphamide metabolites. Aldophosphamide spontaneously converts to phosphoramide mustard and acrolein. Phosphoramide mustard is the active anticancer agent. Acrolein is primarily responsible for the hemorrhagic cystitis complication. The main elimination route of cyclophosphamide and its metabolites is by renal excretion. Approximately 36-99% of the conventional dose is excreted in the urine within 48 hours with about 5-30% being unchanged drug. Less than 4% of the dose is recovered in feces. Toxicity Dose limiting toxicity is myelosuppression with a nadir of 7-14 days, gastrointestinal side effects, a transient increase in liver enzymes, sterile hemorrhagic cystitis, anorexia, nausea, vomiting, alopecia in susceptible breeds, and infertility. Myelosuppression is exacerbated by other drugs in common chemotherapy combination protocols. Indications Cyclophosphamide is used widely in veterinary medicine for treatment of lymphomas, leukemias, carcinomas and sarcomas in dogs and cats, mainly in combination protocols. Cyclophosphamide may be prescribed for treatment autoimmune diseases in veterinary medicine. 58
58° Congresso Nazionale SCIVAC • Milano, 7-9 Marzo 2008 • Oncologia veterinaria - Alle soglie del III Millennio Contraindications Myelosuppression, characterized by leukopenia and thrombocytopenia, necessitates dose delay. Treatment should be interrupted in patients who develop infections. Because of the importance of renal excretion, patients with renal failure should receive alternative alkylating agents or should have the dose reduced or interval increased. Guidelines for dose modification in the face of renal insufficiency have not been well established. Patients that develop sterile hemorrhagic cystitis should discontinue the use of cyclophosphamide, or should only receive the drug concurrently with the urothelial protectant compound 2-mercaptoethanesulphonate (mesna). Therapy should be discontinued in case of anaphylactic reactions, or known sensitivity. CHLORAMBUCIL Chlorambucil is an aromatic derivative of mustargen. It is the slowest acting and generally least toxic of the commonly used alkylating agents. Mechanism of action As with other classical alkylating agents, chlorambucil preferentially binds the 7-N position of guanine. Chlorambucil is a bifunctional alkylator in that it can bind to two DNA strands as well as DNA and a macromolecule. DNA damage includes base mispairing, DNA template misreading, and spontaneous depurination. Pharmacokinetics Chlorambucil is readily absorbed after oral administration, leading to peak plasma levels after 2-4 hours. Food can interfere with absorption. The dose used in veterinary medicine ranges from 2-6 mg/m 2 PO given every other day, or up to 20 mg/m 2 PO administered every 3 weeks. Chlorambucil is metabolized in the liver to an alkylating metabolite, phenyl-acetic acid mustard, which is degraded before being excreted by the kidneys. Chlorambucil is extensively protein bound. Toxicity Bone marrow suppression is the most significant side effect. Myelosuppression secondary to chlorambucil seems to be less severe than that of cyclo- 59
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