| 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 carcinogenesis. 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 similar drugs 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. |
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Nitrogen Mustards: |
| The most common subgroup of alkylating agents used is the nitrogen mustard group. Mechlorethamine hydrochloride is the prototype of the nitrogen mustards and has been used to treat Hodgkin’s disease in humans, mycosis fungoides, lymphoreticular neoplasia, and pleural and peritoneal effusions. Because of its highly unstable nature and extremely short duration of action, mechlorethamine is not widely used in veterinary
medicine. Derivatives of mechlorethamine that are commonly used include cyclophosphamide, chlorambucil, and less frequently, 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. Sterile hemorrhagic cystitis caused by acrolein, a metabolite of cyclophosphamide, can develop and should be treated by active diuresis and intravesicular
administration of N-acetylcysteine. Mesna, a drug that acts to detoxify metabolites of cyclophosphamide, has been used in human medicine to preclude hemorrhagic cystitis. An analog of cyclophosphamide, ifosphamide, is available but is not currently used as a front-line drug in veterinary medicine. |
| 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, but this is usually late in onset and rapidly reversible. 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. |
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Melphalan, an L-phenylalanine derivative of mechlorethamine, is given PO or IV and is primarily used in veterinary medicine to treat multiple myeloma. |
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| Other Alkylating Agents: |
| Of the other subgroups of alkylating agents, several have limited but specific uses.
Triethylenethiophosphoramide, an ethylenimine, may be used intravesicularly in the treatment of 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,
carmustine and
lomustine, readily cross the blood-brain barrier and have been useful in management of CNS neoplasias.
Dacarbazine, a triazene derivative, has been used in combination with doxorubicin for treatment of relapsed canine lymphoma. |
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