Alkylating Agents

Cyclophosphamide

Prodrug requiring hepatic metabolism for activation, relatively sparing of megakaryocytes and hematopoietic stem cells; bifunctional alkylator, nitrogen mustard class

Lymphoma, mammary adenocarcinoma and other carcinomas, sarcomas, lymphoid leukemias, metronomic chemotherapy

Nausea, vomiting, moderate to severe myelosuppression, sterile hemorrhagic cystitis

PO, IV

Ifosfamide

Analogue of cyclophosphamide; requires hepatic biotransformation for activation; bifunctional alkylator, nitrogen mustard class

Various sarcomas, particularly leiomyosarcoma

Nausea, vomiting, myelosuppression, sterile hemorrhagic cystitis, possible nephrotoxicosis

IV with saline diuresis and mesna to prevent hemorrhagic cystitis

Chlorambucil

Does not require hepatic metabolism for activation; bifunctional alkylator; considered slow-acting alkylating agent, nitrogen mustard class

Chronic lymphocytic leukemia, small-cell lymphoma, metronomic chemotherapy

Nausea, vomiting, diarrhea, mild to moderate myelosuppression, cumulative thrombocytopenia

PO

Melphalan

Does not require biotransformation for activation; bifunctional alkylator, nitrogen mustard class

Multiple myeloma, anal gland carcinoma

Nausea, vomiting, diarrhea, anorexia, moderate myelosuppression (may be more myelosuppressive in cats)

PO, IV

Lomustine (CCNU^a)

Highly lipid soluble and able to cross blood-brain barrier; bifunctional alkylating agent, nitrosourea class

Lymphoma, mast cell tumors, histiocytic sarcomas, CNS neoplasms, multiple myeloma

Nausea, vomiting, diarrhea, moderate to severe myelosuppression (may be delayed for 4–6 wk, particularly in cats), hepatotoxicosis (dogs), nephrotoxicosis, cumulative pulmonary toxicosis

PO

Streptozotocin

High affinity for pancreatic beta cells; nitrosourea class; also classified as antitumor antimicrobial (Streptomyces product)

Insulinoma

Severe, potentially fatal nephrotoxicosis (if administered without diuresis) and hepatotoxicosis, nausea (immediate and delayed), vomiting, diarrhea, mild myelosuppression, diabetes mellitus

IV infusion with diuresis

Dacarbazine

Requires hepatic biotransformation for activation; monofunctional alkylator, nonclassical class

Lymphoma, sarcomas, melanoma (often combined with anthracycline)

Severe acute nausea, vomiting, diarrhea, phlebitis, moderate myelosuppression, hepatotoxicosis, pleural effusion in cats (anecdotal)

IV infusion

Temozolomide

Imidazotetrazine derivative of dacarbazine; able to cross blood-brain barrier; monofunctional alkylator, nonclassical class

Lymphoma, sarcomas, melanoma, gliomas and other brain tumors

Nausea, vomiting, diarrhea, mild to moderate myelosuppression

PO

Cisplatin

Platinum molecule with two chloride ligands and two ammonium ions; causes methylation with some bifunctional alkylating activity; nonclassical alkylator class

Osteosarcoma, carcinomas, mesothelioma, malignant effusions (intracavitary)

Intense nausea, vomiting, diarrhea, mild to moderate myelosuppression, potentially fatal nephrotoxicosis if administered without diuresis, anaphylaxis, ototoxicosis, peripheral neuropathy; cannot be administered to cats (fulminant pulmonary edema)

IV or intracavitary, with vigorous saline diuresis; intralesional (including beads in horses)

Carboplatin

Analogue of cisplatin; monofunctional and bifunctional alkylator, nonclassical alkylator class

Osteosarcoma, carcinomas

Mild nausea, vomiting, diarrhea, moderate to severe myelosuppression, rare ototoxicosis/deafness; safe for cats

IV

Antimetabolites

Rabacfosadine

Guanine analogue; inhibits DNA polymerases and thereby DNA synthesis

Lymphoma (FDA approved for dogs)

Nausea, vomiting, mild to moderate myelosuppression, hepatoxicosis and possibly nephrotoxicosis, dermatopathy, cumulative pulmonary fibrosis (may be idiosyncratic)

IV infusion

Cytarabine

Pyrimidine analogue; incorporates into DNA, resulting in steric hindrance and inhibition of DNA synthesis

Lymphoma (including CNS), leukemias, CNS inflammatory disease; no activity in solid tumors

Nausea, vomiting, moderate myelosuppression, nephrotoxicosis, hepatotoxicosis

IV infusion, SC

5-Fluorouracil

Pyrimidine analogue; interferes with DNA synthesis and incorporates into RNA; binds thymidylate synthase

Carcinomas, particularly GI and cutaneous (systemic); cutaneous carcinomas, particularly squamous cell carcinomas (topical)

Systemic: nausea, vomiting, moderate myelosuppression, GI ulceration, neurotoxicosis, hepatotoxicosis

Topical: local irritation, pain, hyperpigmentation

Cannot be administered to cats (fatal neurotoxicosis)

IV; topical (horses)

Gemcitabine

Pyrimidine analogue; incorporates into DNA, resulting in steric hindrance and inhibition of DNA synthesis

Limited efficacy observed in lymphoma and various carcinomas

Mild nausea, vomiting, mild to moderate myelosuppression, pulmonary toxicosis, nephrotoxicosis

IV

Methotrexate

Folic acid analogue; inhibits DNA synthesis and repair by blocking the formation of tetrahydrofolate

Lymphoma, immune disorders

Nausea, vomiting, moderate myelosuppression, GI ulceration, hepatotoxicosis, pulmonary toxicosis

IV, PO, intrathecal

Antineoplastic Antimicrobials

Doxorubicin

Disrupts DNA helical structure and template function: directly alkylates DNA; inhibits DNA and RNA polymerases and helicase, promotes cleavage of DNA by topoisomerase II beta, generates reactive oxygen species, and interacts with the plasma membrane; anthracycline antimicrobial

Lymphoma, leukemias, multiple myeloma, osteosarcoma, hemangiosarcoma, and various other sarcomas and carcinomas

Nausea, vomiting, moderate myelosuppression, hemorrhagic colitis, severe cutaneous reactions if extravasated; red urine (not hematuria), transient ECG changes and arrhythmias, nephrotoxicosis, anaphylactoid reactions; cumulative dose-related cardiomyopathy in dogs; cumulative nephrotoxicosis in cats

IV infusion over 15–30 min

Mitoxantrone

Synthetic anthracenedione derivative of doxorubicin; promotes cleavage, aggregation, oxidation, and strand breakage of DNA

Lymphoma, various carcinomas; often substituted for doxorubicin when risk of cardiotoxicosis is a concern

Nausea, vomiting, moderate to severe myelosuppression, diarrhea, bluish discoloration to sclera; adverse effects less severe than for others in this group

IV

Bleomycin

Mixture of glycopeptides; generates oxygen radicals that cause cleavage and fragmentation of DNA

Carcinomas, acanthomatous ameloblastoma, malignant effusions

Nausea, vomiting, myelosuppression, fever, allergic reactions including anaphylaxis, hyperpigmentation, skin ulceration, pneumonitis, pulmonary fibrosis

SC, intralesions (odontogenic tumors), intracavitary

Mitotic Inhibitors

Vinblastine

Vinca alkaloid

Lymphoma and leukemias, mast cell tumors, transitional cell carcinoma

Mild nausea, vomiting, moderate to severe myelosuppression, neurotoxicosis with high doses, extravasation reactions, inappropriate secretion of antidiuretic hormone

IV

Vincristine

Vinca alkaloid derived from periwinkle plant

Lymphoma and leukemias, transmissible venereal cell tumors, various sarcomas

Mild to moderate nausea, vomiting, mild to moderate myelosuppression, severe tissue reaction if extravasated, cumulative peripheral neuropathy, constipation, paralytic ileus, inappropriate secretion of antidiuretic hormone

IV

Vinorelbine

Synthetic vinca alkaloid

Primary lung tumors, limited efficacy in mast cell tumors

Mild nausea, vomiting, myelosuppression

IV

Paclitaxel

Taxane

Mammary carcinomas, squamous cell carcinomas

Myelosuppression, nausea, vomiting, hypersensitivity (when polyethoxylated castor oil base is used as vehicle) requiring prophylaxis and often dose limiting

IV

Hormones

Prednisone

Glucocorticoid steroid; lympholytic: induces apoptosis and inhibits mitosis in lymphocytes

Lymphoid malignancies (lymphoma, leukemias, plasmacytoma, multiple myeloma), mast cell tumors; palliative treatment of brain tumors

Polyuria/polydipsia, polyphagia, GI ulceration, protein catabolism, delayed wound healing, suppression of hypothalamic-pituitary-adrenal axis, immunosuppression, peripheral insulin resistance

PO

Miscellaneous

l-Asparaginase

Enzyme that cleaves asparagine to deplete circulating concentrations of this amino acid; G₁ phase–specific drug based on inhibition of protein synthesis in cells lacking sufficient concentrations of asparagine synthetase (eg, malignant immature lymphocytes)

Acute lymphoid leukemias and lymphoma

Hypersensitivity reactions, anaphylaxis especially after repeated doses, alteration in coagulation parameters, hepatotoxicosis, potential inhibition of immune responsiveness (B and T cells)

SC, IM

Mitotane (o,p′DDD)

Derivative of the pesticide DDT; has selective direct cytotoxic effects on adrenal cortical cells; inhibits steroid production

Pituitary-dependent hyperadrenocorticism, adrenal cortical tumors

Nausea, vomiting, anorexia, diarrhea, adrenal insufficiency, CNS depression, dermatitis

PO

Hydroxyurea

Inhibits conversion of ribonucleotides to deoxyribonucleotides by inhibiting ribonucleoside diphosphate reductase

Polycythemia vera, granulocytic and basophilic leukemia, essential thrombocythemia; investigational for meningiomas

Nausea, vomiting, myelosuppression, alopecia, sloughing of claws, dysuria, potential hepatotoxicosis

PO

Procarbazine

Mechanism is unclear; inhibits DNA, RNA, and protein synthesis, likely through alkylation; crosses blood-brain barrier

Lymphoma, as part of MOPP^b chemotherapy protocol; brain tumors and inflammatory lesions

Nausea, vomiting, myelosuppression, diarrhea

PO