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Miscellaneous Antineoplastic Agents

By Lisa G. Barber, DVM, Cummings School of Veterinary Medicine, Tufts University ; Kristine E. Burgess, DVM, DACVIM (Oncology), Cummings School of Veterinary Medicine, Tufts University

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 hydrolysis 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 synthesis 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 to prevent this acute toxic reaction. Anti-asparaginase antibody production may also account for 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 monomethoxypolyethylene 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 two chloride ions and two 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 antitumoral 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 adverse 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 osteosarcoma. 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 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.

Epipodophyllotoxins 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 two drugs in this class, etoposide and teniposide, the former has been used primarily in 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.

Biologic Response Modifiers in Cancer Therapy:

In recent years, a number of alternative modes of cancer therapy have become increasingly available in veterinary medicine. These novel forms of therapy work in myriad ways, including enhanced immune recognition, altered blood vessel formation, or by exploitation of specific pathways that are aberrant or overexpressed in neoplastic cells. The widespread use of these newer therapies alone or in combination with conventional chemotherapy has transformed the approach to treatment of many cancer patients.

NSAIDs represent one class of biologic response modifiers that work by inhibiting frequently overexpressed COX-2 enzyme activity present in many tumor types. Several studies have proposed that these drugs may work by reducing cell proliferation, increasing apoptosis, inhibiting angiogenesis, and modulating immune function. Piroxicam has been the drug most researched in dogs, but any of the newer NSAIDs with more COX-2 selective inhibition (such as deracoxib or meloxicam) theoretically may yield equal or improved effects. (See also Nonsteroidal Anti-inflammatory Drugs.) The clinical usefulness of COX-2 inhibitors has been demonstrated in canine transitional cell carcinoma, squamous cell carcinoma, and other tumor types in dogs and cats. NSAIDs are often combined in antiangiogenic protocols.

Metronomic or antiangiogenic dosing of chemotherapy is a novel or nontraditional way to administer chemotherapy that consists of the administration of low doses of oral chemotherapy agents at very short intervals, often daily. This treatment approach targets the tumor neovasculature by leveraging the exquisite sensitivity of endothelial progenitor cells and immature endothelium to modest doses of alkylating agents. Studies indicate that antiangiogenic factors, such as thrombospondin-1, increase during metronomic chemotherapy. In addition, antitumor immunosuppression mediated through T regulatory cells may be mediated by metronomic protocols. Disease stabilization is considered a successful outcome of low-dose chemotherapy, because direct cytotoxicity to neoplastic cells is not the intent of metronomic chemotherapy. Preliminary studies in the veterinary literature suggest this is a promising alternative to maximally tolerated doses of conventional chemotherapy, particularly in a microscopic disease setting, and has the added benefit of limited adverse effects.

Targeting of specific pathways that are aberrant or dysregulated in cancers has yielded novel therapies in a variety of human cancers. An example of such a target is the receptor tyrosine kinases (RTKs), which mediate processes involved in tumor growth, progression, and metastasis. These drugs are competitive inhibitors of ATP, and so prevent receptor phosphorylation and subsequent downstream signal transduction. Mutations in c-kit, an RTK gene involved in mast cell differentiation and proliferation, has been reported in approximately a quarter of canine mast cell tumors. Toceranib has been approved by the FDA, and biologic response rates of 70%–90% have been reported in dogs that have mast cell tumors with recognized c-kit mutations. Moreover, toceranib has activity against other members of the split-kinase family of RTKs, such as vascular endothelial growth factor receptor, platelet-derived growth factor, and others. Preliminary evidence indicates that toceranib has activity against a variety of carcinomas and metastatic osteosarcoma, leading to tumor regression or more often to prolonged disease stabilization. Recent reports indicate that dosages of toceranib ranging from 2.4–2.9 mg/kg, PO, every 48 hr (below the label dosage of 3.25 mg/kg, PO, every 48 hr) result in sufficient target inhibition with substantially reduced toxicity.

Development of a therapeutic vaccine to stimulate active immunity against cancer has long been a goal in both human and veterinary oncology. This became a reality with introduction of a canine melanoma vaccine. The vaccine exploits the immune response induced by human tyrosinase, an enzyme in the pathway of melanin formation. The vaccine contains a human tyrosinase gene inserted into a bacterial plasmid, which is administered transdermally. The antibodies and T-cell responses produced by xenogeneic tyrosinase cross-react with the tyrosinase overexpressed on canine melanoma cells. Initial studies reported prolonged survival in dogs with advanced stage oral malignant melanoma treated with radiation therapy or surgery of the primary tumor, followed by vaccine administration.

Passive immunotherapy using monoclonal antibodies has grown substantially in human oncology in recent years. Monoclonal antibodies may attach to specific antigens on cancer cells, thereby either marking the cancer cells for destruction by the immune system or impairing functional pathways within the neoplastic cells. Furthermore, monoclonal antibodies may be conjugated to other antineoplastic agents (such as chemotherapy agents, radionuclides, or other toxins) to allow for more targeted delivery of cytotoxic therapy to cancer cells while sparing normal tissues. The introduction of anti-CD20 monoclonal antibodies in human oncology has revolutionized the treatment of B-cell lymphoma with significantly improved outcomes versus chemotherapy alone. In veterinary medicine, anti-CD20 and anti-CD52 monoclonal antibodies have received either USDA or conditional approval to treat canine B-cell and T-cell lymphoma, respectively. The mechanisms by which these antibodies work is not fully understood, but several potential mechanisms include antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and direct signaling leading to inhibition of proliferation or to apoptosis. Field studies of each of these antibodies are underway.

Biologic response modifiers aimed at enhancing innate antitumor defense mechanisms of the host has been an area of active investigation. Nonspecific immunomodulators, including intact bacteria or bacterial cell components, acemannan, IL-2, IL-12, interferon alpha, levamisole, and cimetidine, have been reported with variable efficacy to enhance immune responsiveness and improve outcomes after surgery or antineoplastic chemotherapy. Liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) is perhaps the best studied nonspecific immunomodulator in veterinary medicine. This synthetic bacterial wall component has been used effectively with chemotherapy to confer a survival advantage in dogs with splenic hemangiosarcoma and osteosarcoma.

Development of immunomodulators such as lymphokines and cytokines (eg, interleukins, interferon, and tumor necrosis factor) for clinical use in cancer patients has not been fully realized, largely because of toxicity. Consequently, these agents are not commonly used in veterinary medicine.

Blocking angiogenesis is an attractive form of anticancer therapy, because tumors must develop their own vascular supply if they are to grow beyond a few millimeters in diameter. Various drugs, such as angiostatin, thrombospondin-1, and matrix metalloproteinase inhibitors, have been investigated with varying results. Specific angiogenesis inhibitors for veterinary patients are not yet commercially available. At present, metronomic chemotherapy combinations are the most practical approach to antiangiogenic therapy in clinical cases.