THE MERCK VETERINARY MANUAL
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Miscellaneous Antineoplastic Agents

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Several drugs used as antineoplastics do not fall into any of the categories mentioned thus far. These include l-asparaginase, cisplatin, mitotane (o,p′DDD), hydroxyurea, etoposide, and procarbazine.

l-asparaginase is an enzyme derived from Escherichia coli that catalyzes hydro-lysis of asparagine. Because some tumor cells have poor expression of asparagine synthetase and are unable to produce the amino acid asparagine, treatment with this drug deprives these cells of exogenously supplied asparagine and ultimately limits protein synthesis. Because protein syn-thesis is active in the G1 phase of the cell cycle, l-asparaginase is considered to be a G1 phase-specific drug. Preferred routes of administration for l-asparaginase include IM and SC. Anaphylaxis on repeated administration of l-asparaginase may occur as a result of host anti-asparaginase antibody production; pretreatment of animals with antihistamine helps prevent this acute toxic reaction. Anti-asparaginase antibody production may also account for the development of tumor resistance, as can a decreased tumor cell requirement for asparagine. A related drug, pegaspargase, is modified from l-asparaginase by covalent modification with mono-methoxypolyethylene glycol. The conjugated drug produces fewer hypersensitivity reactions than does l-asparaginase.

Cisplatin (cis-diamine-dichloroplatinum) functions primarily as a bifunctional alkylator but is included in the miscellaneous category because of its unusual structure. It is a platinum ion complexed to 2 chloride ions and 2 ammonium molecules. Cisplatin causes inter and intrastrand DNA cross-linking that disrupts DNA helices and prevents DNA synthesis. Cisplatin is cell-cycle nonspecific and has been used both for its direct anti-tumor and radiation sensitizing effects. It is administered by IV drip in combination with aggressive saline diuresis. Excretion is prolonged, with up to 50% of a dose still present in the body 5 days after administration. Extreme, dose-limiting, proximal tubular renal necrosis typifies the delayed side effects of cisplatin along with other responses that may include ototoxicity, moderate bone marrow suppression, peripheral neuropathy, and renal potassium and magnesium wasting. Cisplatin causes fatal pulmonary edema in cats and must not be used in this species.

Because of the extreme toxic adverse effects of cisplatin, newer generation derivatives such as carboplatin and others have been developed. Carboplatin is effective as an adjunct to surgery for treatment of osteo-sarcoma. Nausea and vomiting are less severe than with cisplatin, and carboplatin is not considered nephrotoxic. It is, however, myelosuppressive, with neutropenia being the dose-limiting toxicity. Carboplatin is excreted through the kidneys; consequently dogs or cats with evidence of compromised renal function require dose adjustments to avoid excessive toxicity. Carboplatin is considered safe for administration to cats.

Mitotane (o,p′DDD), a derivative of the insecticides DDT and DDD, causes selective destruction of normal and neoplastic adrenal cortical cells. Mitotane may act by inhibiting production of steroids induced by adrenocorticotropic hormone, which causes atrophy of the inner zones of the adrenal cortex. Mitotane is administered PO, and plasma concentrations can be detected for several weeks.

Hydroxyurea, a simple hydroxylated derivative of urea, is most commonly used in the treatment of polycythemia vera. Hydroxyurea inhibits ribonucleoside diphosphate reductase (RNDR), limits the conversion of ribonucleotides to deoxyribonucleotides, and blocks DNA synthesis. Cells are arrested in the G1-S interface. Mechanisms of resistance include amplification of the RNDR gene or development of RNDR with reduced sensitivity to hydroxyurea. Loss of claws has been associated with hydroxyurea use in animals.

Epidodophyllotoxins are semisynthetic glycosides of podophyllotoxin derived from the mandrake plant. Although these toxins bind tubulin, their mechanism of action is unrelated to disruption of microtubules. Instead, they are thought to stimulate DNA cleavage mediated by topoisomerase II. Of the 2 drugs in this class, etoposide and teniposide, the former has been used primarily in the treatment of testicular carcinoma.

Procarbazine is considered to function as an alkylating agent but is included in the miscellaneous category because the exact mechanism of action is not known. It is typically used as part of the MOPP protocol that includes mechlorethamine, vincristine (tradename Oncovin®), procarbazine, and prednisone for dogs with lymphoma. This drug is metabolized and activated in the liver. GI toxicity and myelosuppression are the primary concerns associated with the MOPP protocol.

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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