These anthracycline antibiotics are among the most important antitumor agents. They are derived from the fungus Streptococcus peucetius var. caesius. Idarubicin and epirubicin are analogs of the naturally produced anthracyclines, differing only slightly in chemical structure, but having somewhat distinct patterns of clinical activity. Daunorubicin and idarubicin have been used primarily in the acute leukemias, whereas doxorubicin and epirubicin display broader activity against human solid tumors. These agents, which all possess potential for generating free radicals, cause an unusual and often irreversible cardiomyopathy that is related to the total dose of the drug. The structurally similar agent mitoxantrone (an anthracenedione) has useful activity against prostate cancer and AML, is used in high-dose chemotherapy, and has significantly less cardiotoxicity than do the anthracyclines.
The anthracycline antibiotics have a tetracyclic ring structure attached to an unusual sugar, daunosamine. Cytotoxic agents of this class all have quinone and hydroquinone moieties on adjacent rings that permit the gain and loss of electrons. A number of important biochemical effects have been described for the anthracyclines and anthracenediones, all of which could contribute to their therapeutic and toxic effects. These compounds can intercalate with DNA, directly affecting transcription and replication. A more important action is the ability of these drugs to form a tripartite complex with topoisomerase II and DNA. Formation of the tripartite complex with anthracyclines and with etoposide inhibits the religation of the broken DNA strands, leading to apoptosis. Defects in DNA double-strand break repair sensitize cells to damage by these drugs, while overexpression of transcription-linked DNA repair may contribute to resistance. Anthracyclines can form semiquinone radical intermediates, which in turn can react with oxygen to produce superoxide anion radicals. These can generate both hydrogen peroxide and hydroxyl radicals (OH), which attack DNA and oxidize DNA bases. The production of free radicals is significantly stimulated by the interaction of doxorubicin with iron. Enzymatic defenses such as superoxide dismutase and catalase are believed to have an important role in protecting cells against the toxicity of the anthracyclines, and these defenses can be augmented by exogenous antioxidants such as a tocopherol or by an iron chelator, dexrazoxane (zinecard), which protects against cardiac toxicity. Exposure of cells to anthracyclines leads to apoptosis.
Multidrug resistance is observed in tumor cell populations exposed to anthracyclines. Attempts to reverse or prevent the emergence of resistance through the simultaneous use of inhibitors of P-glycoprotein, such as Ca2+ channel blockers, steroidal compounds, and others, have yielded inconclusive results, primarily because of the effects of these inhibitors on anthracycline phar-macokinetics and metabolism. Anthracyclines also are exported from tumor cells by members of the MRP transporter family and by the breast cancer resistance protein. Other biochemical changes in resistant cells include increased glutathione peroxidase activity, decreased activity or mutation of topoisomerase ii, and enhanced ability to repair DNA strand breaks.
Daunorubicin, doxorubicin, epirubicin, and idarubicin usually are administered intravenously. Careful infusion over 10—15 minutes is recommended to prevent extravasation, since severe local vesicant action may result. The drugs are cleared by a complex pattern of hepatic metabolism and biliary excretion. The plasma disappearance curve for doxorubicin is multipha-sic, with elimination half-lives of 3 hours and ~30 hours. All anthracyclines are converted to an active alcohol intermediate that plays a variable role in their therapeutic activity. idarubicin has a t122 of ~15 hours, and its active metabolite, idarubicinol, has a t122 of ~40 hours. There is rapid uptake of the drugs in the heart, kidneys, lungs, liver, and spleen. They do not cross the blood—brain barrier. Daunorubicin and doxorubicin are eliminated by metabolic conversion to a variety of aglycones and other inactive products. idarubicin is primarily metabolized to idarubi-cinol, which accumulates in plasma and likely contributes significantly to its activity. Clearance is delayed in the presence of hepatic dysfunction, and at least a 50% initial reduction in dose should be considered in patients with elevated serum bilirubin levels.
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