Cardiotoxicity daunorubicin

Daunorubicin -anthracycline antitumor antibiotic DNA intercalating agent -bone marrow suppression -nausea and vomiting—mild to moderate -mucocutaneous effects (mucositis, stomatitis, diarrhea) -vesicant if extravasated —cardiotoxicity (550 mg/M2) -Liposomal daunorubicin there is significantly less bone marrow suppression, nausea and vomiting, stomatitis, and cardiotoxicity... 

Anthracyclines (daunorubicin, doxorubicin, idarubicin, and epirubicin) are anticancer drugs widely used to manage patients with acute leukemia or breast cancer.22-23 To maximize therapeutic efficacy and minimize the acute myelosuppression and cumulative dose-related cardiotoxicity of these agents, several analytical methods were developed to measure anthracyclines and their metabolites in biologic fluids,24 26... 

The anthracycline antibiotics, which include doxorubicin, daunorubicin, bleomycin, and mitomycin C, inhibit DNA and RNA synthesis. Doxorubicin also interfers with topoisomerase II (a DNA gyrase), the activity of which is markedly increased in proliferating cells. Structurally related to doxorubicin are epirubicin and mitozantrone. The cytotoxic antibiotics are used to treat leukaemias and lymphomas and also for solid tumours in the breast, lung, thyroid and ovary. Cardiotoxicity is the major dose-limiting factor, with arrhythmias and myocardial depression (Bacon and Nuzzo 1993). The chronic phase of cardiotoxicity is a dose-dependent cardiomyopathy that leads to congestive heart failure in 2-10% of patients. Myocardial injury is the result of oxygen free radical formation. Children are particularly sensitive to these cardiotoxic reactions and may require a heart transplant in their later years. Epirubicin is less cardiotoxic than doxorubicin. 

Daunorubicin Oxygen free radicals bind to DNA causing single- and double-strand DNA breaks inhibits topoisomerase II intercalates into DNA AML, ALL Nausea, fever, red urine (not hematuria) Cardiotoxicity (see text), alopecia, myelosuppression... 

Daunorubicin Cerubidine, DaunoXome Several forms of acute leukemia Blood disorders [anemia, leukopenia, thrombocytopenia] cardiotoxicity [arrhythmias, congestive heart failure] Gl distress [nausea, vomiting, Gl tract ulceration] hair loss... 

Adverse effects Irreversible, dose-dependent cardiotoxicity, apparently a result of the generation of free radicals, is the most serious adverse reaction. Irradiation of the thorax increases the risk of cardiotoxicity. There has been some success with the iron chelator, dexrazone, in protecting against the cardiotoxicity of doxorubicin. As with dactinomycin, both doxorubicin and daunorubicin also cause a transient bone marrow suppression, stomatitis, and Gl tract disturbances. Alopecia is usually severe. 

The development of anthracycline-induced cardiomyopathy is closely related to the cumulative lifetime dose of the anthracycline. The recommended maximum cumulative lifetime dose of doxorubicin is 450-550 mg/m (7) and of daunorubicin 400-550 mg/m intravenously in adults (1,2). About 5% of doxorubicin-treated patients develop congestive cardiac failure at this dose however, the incidence approaches 50% at cumulative doses of 1000 mg/m (7-9). These figures are derived from experience with doxorubicin administered as a bolus or by infusion of very short duration (under 30 minutes). The incidence of clinical cardiotoxicity falls dramatically with other schedules of administration (that is weekly doses or continuous infusion for more than 24 hours). 

A 68-year-old man with relapsed AML presents to the clinic to evaluate further treatment options. He received high-dose chemotherapy (cytarabine and daunorubicin) earlier this year with complications of cardiotoxicity due to the daunorubicin and neurotoxicity from the cytarabine. He has relapsed after a brief remission. Which of the following MoAbs may be considered for use in this patient ... 

Streptomyces coerulerubidos yielded a tetracyclic aminosugar containing an antibiotic named daunorubicin (rubidomycin, Cerubidine ), which exhibited actinomycinlike antitumor activity. Severe cardiotoxicity, however, limited its clinical use, particularly as single agent therapy. 

With the clinical introduction of the 4-demethoxy analog of daunorubicin (idarubicin, Idamycin, Fig. 4-19) in 1991 another set of improvements were achieved. These include higher antileukemic activity, higher potency, and lower cardiotoxicity than the parent compound daunorubicin. The approved indication is acute myelogenous leukemia. 

Daunorubicin (daunomycin, rubidomycin Cerubidine, others) is available for intravenous use. The recommended dosage is 30 to 60 mg/m daily for 3 days. The agent is administered with appropriate care to prevent extravasation, as severe local vesicant action may result. Total doses greater than 1000 mg/m are associated with a high risk of cardiotoxicity. A daunorubicin citrate liposomal product (Daunoxome) is indicated in the treatment of AIDS-related Kaposi s sarcoma. It is given in a dose of 40 mg/m infused over 60 minutes and repeated every 2 weeks. Patients should be advised that the drug may impart a red color to the urine. 

Contrast the cardiotoxicity seen with doxorubicin and daunorubicin. 

Daunorubicin has a lower incidence of cardiotoxicity than doxorubicin. 

Idarubicin is less lipophillic and therefore has less cardiotoxicity than doxorubicin (or daunorubicin). It has a greater affinity for DNA and increased DNA binding compared with doxorubicin and is more readily taken up into target cells. 

Antineoplastic anthracycUne drug (cell cycle-nonspecific) intercalates between base pairs to disrupt DNA functions, inhibits topoisomerases, and forms cytotoxic free radicals. Tox cardiotoxicity (consider dexrazoxane), myelosuppres.sion. Daunorubicin is similar. 

Nausea, vomiting, mucositis, stomatitis, alopecia, bone marrow depression, cardiotoxicity. I I A IV. Rapid, wide distribution, half-life = 6 days. Acute nonlymphocytic leukemia. The usefulness of doxorubicin and daunorubicin is limited by cardiotoxicity. It is hoped that mitoxantrone use will not be limited by cardiotoxicity. 

The absence of the OH group at C14 in daunorubicin (Fig. 42.17) results in a faster conversion to the equally active and chronically cardiotoxic C13-0I metabolite (daunorubicinol) compared to hydroxymethyl-substituted anthracyclines like doxorubicin. The 18.5-hour terminal half-life of daunorubicin is approximately half that of doxorubicin, and the terminal half-life of the active daunorubicinol metabolite is 26.7 hours. Excretion is... 

Shadle SE, Bammel BP, Cusack BJ, Knighton RA, Olson SJ, Mushlin PS, Olson RD (2000) Daunorubicin cardiotoxicity evidence for the importance of the quinone moiety in a free-radical-independent mechanism. Biochem Pharmacol 60 1435-1444 Sicouri S, Antzelevitch C (1991a) A subpopulation of cells with unique electrophysiological properties in the deep subepicardium of the canine ventricle. The M cell. Circ Res 68 1729-1741... 

Despite their usefulness, both daunorubicin and doxorubicin have several acute and long-term side effects. The most severe of these is cumulative cardiotoxicity [14], since it limits the dosage that can be prescribed. In addition, the emergence of multi-drug resistance in cancer cells upon long-term treatment poses serious problems in the clinic. Therefore it is not surpris-... 

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