CYCLOPHOSPHAMIDE
Cyclophosphamide is an alkylating agent; two chloride moieties at opposite ends of the molecule are each capable of covalently
bonding with DNA guanine bases.1,2 This bonding results in attachment of cyclophosphamide to the DNA strand at each reaction site and inhibition of DNA strand
disassociation that must occur during cell division. Because cyclophosphamide-induced DNA cross-linking occurs regardless
of whether a cell is actively undergoing mitosis, cyclophosphamide's effects are cell-cycle independent (in contrast to most
other immunosuppressive drugs). Although this is an advantage when used to treat neoplastic diseases, there may be a higher
likelihood of severe immunosuppression and systemic toxicosis with this drug.
Uses
Although the benefits of cyclophosphamide in multiagent chemotherapy of lymphoma are well-established in veterinary patients,
few studies have evaluated its use in canine or feline immune-mediated diseases. A prospective study of dogs with IMHA treated
with cyclophosphamide demonstrated no benefit over prednisone therapy alone.47 Other, noncontrolled retrospective case series have suggested that two different cyclophosphamide dosing regimens do not
differ in effectiveness or that prognosis may perhaps even be worsened with cyclophosphamide administration.24,48 In the study which suggested a worsened prognosis, cyclophosphamide administration was associated with delayed resolution
of anemia and longer clinical recovery, possibly because of drug-induced suppression of bone marrow stem cells.24 Because of the poor results in adjunctive treatment of IMHA as well as the availability of safer alternatives, cyclophosphamide
has fallen out of favor as an adjunctive treatment option for immune-mediated diseases in dogs and cats.
Adverse effects
The most common side effects of cyclophosphamide in dogs include bone marrow suppression, hemorrhagic cystitis, and gastrointestinal
disturbances. Specific recommendations on how to minimize or treat these drug-associated complications are beyond the scope
of this article, but most veterinary oncology textbooks or chemotherapy references provide this information.
CONCLUSION
At this time, prednisone remains the mainstay drug for immunosuppression in dogs and cats with immune-mediated diseases. However,
alternative lymphocyte-specific immunosuppressive medications are widely used in people with autoimmune diseases and could,
in theory, be effective in veterinary patients as well. These drugs have been successfully used in small numbers of animals,
but prospective studies comparing outcome of patients treated with traditional drug combinations vs. newer immunosuppressants
are lacking. Published or suggested doses that have proven effective in limited numbers of animals are summarized in Table 1. Use of these nonglucocorticoid medications for long-term maintenance of immunosuppression may be reasonable if patients
cannot tolerate or do not respond to currently recommended drugs. However, informed owner consent is strongly recommended,
particularly in regard to the prevalence and severity of drug-associated adverse effects that have been reported in people.
Barrak Pressler, DVM, PhD, DACVIM
Department of Veterinary Clinical Sciences
School of Veterinary Medicine
Purdue University
West Lafayette, IN 47907
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