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Antineoplastic Antibiotics

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

The antineoplastic antibiotics are products of Streptomyces. The important drugs in this group include actinomycin D (dactinomycin), doxorubicin, mitoxantrone, and bleomycin. Drugs less commonly used include daunorubicin, mithramycin, and mitomycin.

Actinomycin A was the first Streptomyces antibiotic isolated and was followed by related antibiotics, including actinomycin D. Actinomycin D binds with double-stranded DNA and blocks the action of RNA polymerase, which prevents DNA transcription. Actinomycin D is considered cell-cycle nonspecific and is given IV but does not cross the blood-brain barrier. Resistance may develop because of decreased cellular uptake of the drug. Occasionally, it is used as a substitute for doxorubicin in dogs with questionable cardiac function or for those dogs that have exceeded the cumulative cardiotoxic dose of doxorubicin.

The anthracycline antibiotics, particularly doxorubicin, have become important antineoplastic antibiotics. These drugs intercalate and bind to DNA between base pairs on adjacent strands. This causes the DNA helix to uncoil, which destroys the DNA template and inhibits RNA and DNA polymerases. Scission of DNA is thought to be mediated by either the enzyme topoisomerase II or by generation of free radicals. Intracellular interactions of anthracycline antibiotics result in the formation of semiquinone radical intermediates capable of generating hydrogen peroxide and hydroxyl radicals. Considered cell-cycle nonspecific because of the damage associated with radical formation, these drugs probably have their maximal effect during the S phase of the cell cycle. The anthracycline antibiotics are given IV; they are severe vesicants if administered perivascularly and may cause a severe, delayed phlebitis. Administration of a free radical scavenger, dexrazoxane, may limit the extent of tissue damage seen with extravasation of this drug. The anthracycline antibiotics are metabolized in the liver to a variety of less active and inactive products.

Doxorubicin toxicity can be manifested in a variety of acute and delayed reactions. Acute effects include hypersensitivity reactions (from nonspecific histamine release), extravasation injury, or transient cardiac arrhythmias. Delayed toxicities can be severe, with the major problem in dogs being cumulative, dose-related cardiac toxicity associated with binding of the drug to cardiac DNA and free radical damage to myocardial membranes. A nonspecific decrease in cardiac fibrils occurs, which leads to congestive heart failure unresponsive to digitalis. Because the cardiotoxic effects of doxorubicin are related to the peak plasma concentrations (rather than area under the curve), slow IV administration over 15–30 min is recommended to help lessen cardiac injury. Myocardial damage from doxorubicin also can be prevented by coadministration of dexrazoxane, at 10 times the dose of doxorubicin. In cats, cumulative doses of doxorubicin can result in nephrotoxicity and should be avoided or used judiciously in cats with preexisting renal insufficiency.

Dose-limiting toxicities of doxorubicin include severe myelosuppression and GI upset. Also, if doxorubicin is used in conjunction with radiation therapy, damage by radiation may be augmented. This radiation sensitization effect may necessitate reduction in radiation or drug dosages, or both. Because of the significant toxicity associated with use of doxorubicin, newer-generation drugs specifically aimed at reduction of cardiac toxicity have been developed and are available in human medicine. Two of these, idarubicin and epirubicin, have been studied, but neither is in common use in veterinary medicine.

A pegylated liposomal encapsulated form of doxorubicin, called doxorubicin HCL liposome injection, has been used effectively in both human and veterinary medicine. The liposomal formulation results in a longer drug circulation time and reduced myelosuppression and cardiotoxicity. In dogs, the dose-limiting toxicity of liposomal doxorubicin is a cutaneous reaction called palmar-plantar erythrodysesthesia. In cats, a delayed nephrotoxicity is the dose-limiting toxicity of both conventional and liposomal doxorubicin.

Mitoxantrone, an anthracenedione related to the anthracycline antibiotics, has shown promise in veterinary medicine for treatment of lymphoma and various carcinomas. The mechanism of action of mitoxantrone is similar to that of the anthracyclines, but most adverse effects are less severe than those of doxorubicin. An exception is myelosuppression, which is more profound with mitoxantrone than doxorubicin.

Bleomycin is actually a mixture of bleomycin glycopeptides that differ only in their terminal amine moiety. The cytotoxic action of these glycopeptides depends on their ability to cause chain scission and fragmentation of DNA molecules. Cells accumulate in the G2 phase of the cell cycle, which accounts for the classification of bleomycin as a G2 and M phase–specific agent. Bleomycin may also affect DNA repair enzymes. Given IV or SC, bleomycin does not cross the blood-brain barrier; a large portion is excreted via the kidneys. Bleomycin has minimal myelosuppressive and immunosuppressive activities but does have an unusual delayed pulmonary toxicity. Pulmonary toxicity, which is cumulative, may begin as a nonspecific pneumonitis that progresses to pulmonary fibrosis. Dangers from pulmonary complications are especially important in older animals with preexisting pulmonary disease.