Antineoplastic antibiotics
From Felipedia
The antineoplastic antibiotics are chemotherapy drugs produced as byproducts of Streptomyces spp bacteria. The important drugs in this group include actinomycin D (dactinomycin), doxorubicin, mitoxantrone, and bleomycin. Drugs less commonly used include daunorubicin, mithramycin, and mitomycin. See Drug doses for individual doses of medications.
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 due to decreased cellular uptake of the drug.
The anthracycline antibiotics, daunorubicin and 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. Urticaria may be seen in the area of the injection and, shortly after administration, erythematous areas may appear along the vein. Recurrence of this response may be prevented by premedication with corticosteroids and antihistamines. 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. Delayed toxicities can be severe, with the major problem 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 that is unresponsive to digitalis. A dose-limiting toxicity of doxorubicin is severe myelosuppression. If doxorubicin is used in conjunction with radiation therapy, damage by radiation may be augmented. This radiation recall effect may necessitate reduction in radiation or drug dosages, or both. Because of the significant toxicity associated with the 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.
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 mitoxanthrone is similar to that of the anthracyclines, but side effects are less severe than those of 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 may begin as a nonspecific pneumonitis that progresses to pulmonary fibrosis. Dangers from pulmonary complications are especially important in older animals with pre-existing pulmonary disease.
