The anthracycline antibiotics are fermentation products of Streptomyces peucetius. Daunorubicin (Cerubidine) is used to treat acute leukemias, while its structural analogue, doxorubicin (Adriamycin) is extensively employed against a broad spectrum of cancers. Although the two drugs have similar pharmacological and toxico-logical properties, doxorubicin is more potent against most animal and human tumors and will be discussed in greater detail.
Doxorubicin binds tightly to DNA by its ability to intercalate between base pairs and therefore is preferentially concentrated in nuclear structures. Intercalation results in steric hindrance, hence production of single-strand breaks in DNA and inhibition of DNA synthesis and DNA-dependent RNA synthesis. The enzyme topoisomerase II is thought to be involved in the generation of DNA strand breaks by the anthracyclines. Cells in S-phase are most sensitive to doxorubicin, although cytotoxicity also occurs in other phases of the cell cycle.
In addition to the intercalation mechanism described, the anthracycline ring of doxorubicin can undergo a one-electron reduction to form free radicals and participate in further electron transfer. These highly active substances can then react with tissue macromol-ecules. This type of interaction suggests an alternative mechanism of cytotoxicity for the anthracyclines. In particular, the cardiac toxicity of anthracyclines may result from the generation of free radicals of oxygen.
Resistance to the anthracyclines usually involves decreased drug accumulation due to enhanced active efflux of drug. This form of drug resistance is common among the large, heterocyclic naturally derived anticancer agents. It is termed multidrug resistance because of the high degree of cross-resistance among the anthracy-clines, vinca alkaloids, dactinomycin, and podophyllo-toxins (see Chapter 55).
Doxorubicin is not absorbed orally, and because of its ability to cause tissue necrosis must not be injected intramuscularly or subcutaneously. Distribution studies indicate rapid uptake in all tissues except the CNS. Extensive tissue binding, primarily intranuclear, accounts for the prolonged elimination half-life. The drug is extensively metabolized in the liver to hydroxylated and conjugated metabolites and to aglycones that are primarily excreted in the bile.
Doxorubicin is one of the most effective agents used in the treatment of carcinomas of the breast, ovary, en-dometrium, bladder, and thyroid and in oat cell cancer of the lung. It is included in several combination regimens for diffuse lymphomas and Hodgkin's disease. Doxorubicin can be used as an alternative to daunoru-bicin in acute leukemias and is useful in Ewing's sarcoma, osteogenic sarcoma, soft-tissue sarcomas, and neuroblastoma. Some activity has been reported in non-oat cell lung cancer, multiple myeloma, and adeno-carcinomas of the stomach, prostate, and testis.
The most important toxicities caused by doxoru-bicin involve the heart and bone marrow. Acutely, doxo-rubicin may cause transient cardiac arrhythmias and depression of myocardial function. Doxorubicin may cause radiation recall reactions, with flare-ups of dermatitis, stomatitis, or esophagitis that had been produced previously by radiation therapy. Less severe tox-icities include phlebitis and sclerosis of veins used for injection, hyperpigmentation of nail beds and skin creases, and conjunctivitis. Because of its intense red color, doxorubicin will impart a reddish color to the urine for 1 or 2 days after administration.
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