THE MERCK VETERINARY MANUAL
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Alkylating Agents

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Alkylating agents form highly reactive intermediate compounds that are able to transfer alkyl groups to DNA. Alkylation can result in miscoding of DNA strands, incomplete repair of alkylated segments (which leads to strand breakage or depurination), excessive cross-linking of DNA, and inhibition of strand separation at mitosis. Monofunctional alkylating agents transfer a single alkyl group and usually result in miscoding of DNA, strand breakage, or depurination. These reactions can result in cell death, mutagenesis, or carcino-genesis. Polyfunctional alkylating agents typically cause strand cross-linking and inhibition of mitosis with consequent cell death. Resistance to one alkylating agent often implies resistance to other drugs in the same class and can be caused by increased production of nucleophilic substances that compete with the target DNA for alkylation. Decreased permeation of alkylating agents and increased activity of DNA repair systems are also common mechanisms of resistance.

Individual alkylating agents are generally cell-cycle nonspecific and can be subgrouped according to chemical structure into nitrogen mustards, ethyleneamines, alkyl sulfonates, nitrosoureas, and triazene derivatives.

The most common subgroup of alkylating agents used is the nitrogen mustard group. Mechlorethamine hydrochloride is the prototype of the nitrogen mustards and is used in veterinary medicine in conjunction with other chemotherapeutic agents to treat lymphoma. Because of its highly unstable nature and extremely short duration of action, the use of mechlorethamine is somewhat limited in veterinary medicine. Derivatives of mechlorethamine that are commonly used for various neoplasias include cyclophosphamide, chlorambucil, and melphalan.

Cyclophosphamide is a cyclic phosphamide derivative of mechlorethamine that requires metabolic activation by the cytochrome P450 oxidation system in the liver. Cyclophosphamide is given PO or IV, and dose-limiting leukopenia associated with bone marrow suppression is the primary toxicity. However, among the alkylating chemotherapy agents, cyclophosphamide's myelosuppressive effect is considered relatively sparing of platelets. Sterile hemorrhagic cystitis may result from aseptic chemical inflammation of the bladder urothelium caused by acrolein, a metabolite of cyclophosphamide. Prevention of this toxicity is key to its management. Concurrent administration of a diuretic, such as furosemide, when cyclophosphamide is given as a single dose may provide a dilutional effect. In addition, cyclophosphamide may be given in the morning so that patients have opportunities to urinate throughout the day in order to minimize contact time of acrolein with the bladder lining. Cyclophosphamide use should be discontinued in patients with evidence of sterile hemorrhagic cystitis. Although the signs may be self-limiting, treatment with fluids, NSAID, and intravesicular DMSO may be considered. Mesna is a drug that binds and inactivates the urotoxic metabolites of cyclophosphamide within the bladder. Mesna that is coadministered with fluid diuresis is recommended when ifosfamide (an analog of cyclophosphamide) or high-dose cyclophosphamide is used.

Chlorambucil, the slowest-acting nitrogen mustard, achieves effects gradually and often can be used in animals with compromised bone marrow. It can cause bone marrow suppression; although it is usually mild, periodic monitoring is recommended with longterm administration. This drug is given PO and is most commonly used in treatment of chronic, well-differentiated cancers; it is considered ineffective in rapidly proliferating tumors.

Melphalan, an L-phenylalanine derivative of mechlorethamine, is given PO or IV and is primarily used in veterinary medicine to treat multiple myeloma.

Of the other subgroups of alkylating agents, several have limited but specific uses. Triethylenethio-phosphoramide (thiotepa), an ethylenimine, has been used as an intravesicular treatment for transitional cell carcinoma of the bladder or as an intracavitary treatment for pleural and peritoneal effusions. Busulfan, an alkyl sulfonate, is used specifically in the treatment of chronic myelocytic leukemia and polycythemia vera. Streptozotocin, a naturally occurring nitrosourea, is used for palliation of malignant pancreatic islet-cell tumors or insulinomas. Other nitrosoureas, such as carmustine and lomustine, readily cross the blood-brain barrier and have been useful in management of lymphoma (including epitheliotropic cutaneous lymphoma), mast cell tumors, histiocytic sarcomas, and CNS neoplasias. Dacarbazine (DTIC), a triazene derivative, has been used either in combination with doxorubicin or as a single agent treatment for relapsed canine lymphoma and soft-tissue sarcomas.

Temozolomide is an oral imidazotetrazine derivative of dacarbazine and belongs to a new class of chemotherapeutic agents that enter the cerebrospinal fluid and do not require hepatic metabolism for activation. In humans, it is used for refractory malignant gliomas and malignant melanomas. There have been reports in the veterinary literature of its use as a substitute for DTIC.

Last full review/revision March 2012 by Deborah T. Kochevar, DVM, PhD, DACVCP; Lisa G. Barber, DVM, DACVIM (Oncology); Kristine E. Burgess, MS, DVM, DACVIM (Oncology)

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