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Mechanisms of Action, Indications, and Toxicities of Selected Antineoplastic Agents

Mechanisms of Action, Indications, and Toxicities of Selected Antineoplastic Agents

Drug

Mechanism of Action

Major Indications

Toxicities

Alkylating Agents

Cyclophosphamide

Undergoes hepatic biotransformation to active metabolites that alkylate DNA; alkylation leads to miscoding of DNA and cross-linking of DNA strands

Lymphoma, mammary adenocarcinoma, sarcomas, lymphocytic leukemia

Nausea, vomiting (infrequent), moderate to severe myelosuppression, sterile hemorrhagic cystitis

Melphalan

Alkylates DNA causing miscoding and cross-linking of DNA strands

Multiple myeloma

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

Chlorambucil

Alkylates DNA causing miscoding and cross-linking of DNA strands; slowest-acting alkylating agent

Chronic lymphocytic leukemia, small-cell lymphoma

Nausea, vomiting, mild to moderate myelosuppression

Lomustine (CCNU)

Alkylates DNA causing miscoding and cross-linking of DNA strands; inhibits both DNA and RNA synthesis; not cross-resistant with other alkylating agents

Lymphoma, mast cell tumor, histiocytic sarcoma, CNS neoplasias, multiple myeloma

Nausea, vomiting, moderate to severe myelosuppression (may be delayed for 4–6 wk), hepatotoxicity, nephrotoxicity, pulmonary toxicity

Streptozotocin

Inhibits DNA synthesis; high affinity for pancreatic β cells

Insulinoma

Severe, potentially fatal nephrotoxicity (if given without diuresis) and hepatotoxicity, nausea (immediate and delayed), vomiting, mild myelosuppression

Dacarbazine (DTIC)

Undergoes hepatic biotransformation to active metabolites that alkylate DNA; inhibits RNA synthesis

Lymphoma, sarcomas

Severe acute nausea, vomiting, phlebitis, moderate myelosuppression, hepatotoxicity, anecdotal reports of pleural effusion in cats

Ifosfamide

Analogue of cyclophosphamide; undergoes hepatic biotransformation to active metabolites that alkylate DNA; alkylation leads to miscoding of DNA and cross-linking of DNA strands

Various sarcomas

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

Antimetabolites

Methotrexate

Inhibition of dihydrofolate reductase that is required for formation of tetrahydrofolate, a necessary cofactor in thymidylate synthesis; thymidylate essential for DNA synthesis and repair

Lymphoma

Nausea, vomiting, moderate myelosuppression, GI ulceration, hepatotoxicity, pulmonary toxicity

5-Fluorouracil

Pyrimidine analogue; interferes with DNA synthesis and may be incorporated into RNA to cause toxic effects

Carcinomas (systemic); cutaneous carcinomas (topical)

Systemic: nausea, vomiting, moderate myelosuppression, neurotoxicity, GI ulceration, neurotoxicity, hepatotoxicity Topical: local irritation, pain, hyperpigmentation Cannot be given to cats (fatal neurotoxicity)

Cytarabine

Pyrimidine analogue; incorporates into DNA causing steric hindrance and inhibition of DNA synthesis

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

Nausea, vomiting, moderate myelosuppression, nephrotoxicity, hepatotoxicity

Gemcitabine

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

Limited efficacy seen in lymphoma and various carcinomas

Mild nausea, vomiting, mild to moderate myelosuppression, pulmonary toxicity, nephrotoxicity

Antibiotic Antineoplastics

Doxorubicin

Intercalates and binds to DNA, disrupting helical structure and DNA template; inhibits RNA and DNA polymerases; causes DNA topoisomerase II–mediated chain scission; generates free radicals that cause DNA scission and cell membrane damage

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, nephrotoxicity, anaphylactoid reactions; Cumulative dose-related congestive heart failure in dogs; cumulative nephrotoxicity in cats

Mitoxantrone

Topoisomerase II–mediated chain scission; DNA aggregation, oxidation, and strand breakage

Lymphoma, various carcinomas

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

Bleomycin

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

Carcinomas

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

Dactinomycin (Actinomycin D)

Intercalates and binds to DNA, disrupting helical structure and DNA template; inhibits RNA and DNA polymerases; causes DNA topoisomerase II–mediated chain scission; generates free radicals that cause DNA scission and cell membrane damage

Lymphoma, various sarcomas

Nausea, vomiting, moderate to severe myelosuppression, phlebitis; severe tissue reaction if extravasated

Mitotic Inhibitors

Vinblastine

Binds to tubulin, leading to disruption of mitotic spindle apparatus and arrest of cell cycle

Lymphoma and leukemias, mast cell tumors

Mild nausea, vomiting, severe myelosuppression, neurotoxicity with high doses, inappropriate secretion of antidiuretic hormone

Vincristine

Binds to tubulin, leading to disruption of mitotic spindle apparatus and arrest of cell cycle

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

Vinorelbine

Binds to tubulin, leading to disruption of mitotic spindle apparatus and arrest of cell cycle

Primary lung tumors, limited efficacy in mast cell tumors

Mild nausea, vomiting, myelosuppression

Paclitaxel

Binds to tubulin, stabilizing microtubule polymer and arresting mitosis

Mammary carcinoma, squamous cell carcinoma

Myelosuppression, nausea, vomiting, hypersensitivity (when Cremor EL is used as vehicle)

Miscellaneous

Cisplatin

Reacts with proteins and nucleic acids; forms cross-links between DNA strands and between DNA and protein; disrupts DNA synthesis

Osteosarcoma, carcinomas, and mesothelioma

Intense nausea, vomiting, mild to moderate myelosuppression, potentially fatal nephrotoxicity if not given with diuresis, anaphylaxis, ototoxicity, peripheral neuropathy, hyperuricemia, hypermagnesemia; Cannot be given to cats (fulminant pulmonary edema)

Carboplatin

Reacts with proteins and nucleic acids; forms cross-links between DNA strands and between DNA and protein; disrupts DNA synthesis

Osteosarcoma, carcinomas

Mild nausea, vomiting, diarrhea, moderate to severe myelosuppression

l-Asparaginase

Inhibits protein synthesis by hydrolyzing tumor cell supply of asparagine

Acute lymphoid leukemias and lymphoma

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

Mitotane (o,p′DDD)

Destroys adrenal zona fasciculata and zona reticularis

Pituitary hyperadrenocorticism, palliation of adrenal cortical tumors

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

Hydroxyurea

Inhibits conversion of ribonucleotides to deoxyribonucleotides by destroying ribonucleoside diphosphate reductase

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

Nausea, vomiting, mild myelosuppression, alopecia, sloughing of claws, dysuria

Procarbazine

Mechanism is unclear; inhibits DNA, RNA, and protein synthesis, perhaps through alkylation

Lymphoma, as part of MOPP chemotherapy protocol; brain tumors

Nausea, vomiting, myelosuppression, diarrhea

Hormones

Prednisone

Lympholytic; inhibits mitosis in lymphocytes

Lymphoma, mast cell tumors, multiple myeloma, palliative treatment of brain tumors

Sodium retention, GI ulceration, protein catabolism, muscle wasting, delayed wound healing, suppression of hypothalamic-pituitary-adrenal axis,immunosuppression