Daunorubicin actions

K Osann, P Sweet, LM Slater. (1992). Synergistic action of cyclosporin A and verapamil on vincristine and daunorubicin resistance in multidrug-resistant human leukemia cells in vitro. Cancer Chemother Pharmacol 30 152-154. 

Gewirtz, D. A, 1999, A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracychne antibiotics adriamycin and daunorubicin. Biochem. Pharmacol. 57 727-741... 

The mechanism of action of daunorubicin and the indications for use are exactly the same as those of doxorubicin. Synonyms of this drug are daunoblastina, rabomycin, and cerubidine. 

In Fig. 1 various targets of some important cytostatic agents are depicted. Their main mechanisms of action can be briefly summarized as follows. Pentostatin blocks purine nucleotides by inhibiting adenosine deaminase. 6-Mercaptopurine and 6-thioguanine inhibit purine ring biosynthesis and they inhibit nucleotide interconversions. Methotrexate by inhibiting dihydrofolate reduction blocks thymidine monophosphate and purine synthesis. 5-Fluorouracil also blocks thymidine monophosphate synthesis. Dactinomycin, daunorubicin, doxorubicin and mitoxantrone intercalate with DNA and inhibit RNA synthesis. L-asparaginase deaminates... 

Idarubicin (Idamycin) differs from its parent compound, daunorubicin, by the absence of the methoxy group in the anthracycline ring structure. Its mechanisms of action and resistance are similar to those of doxorubicin and daunorubicin however, it is more lipophilic and more potent than these other anthracy-clines. Idarubicin undergoes extensive hepatic metabolism and biliary excretion. Adverse reactions of idarubicin are similar to those of its congeners. 

Therapeutic applications Applications for these two agents differ despite their structural similarity and their apparently similar mechanisms of action. Doxorubicin is one of the most important and widely used anticancer drugs. It is used for treatment of sarcomas and a variety of carcinomas, including breast and lung, as well as acute lymphocytic leukemia and lymphomas. Daunorubicin is used in the treatment of acute lymphocytic and myelocytic leukemias. 

Figure 3.1 Combined effects of a combination of 7 anticancer drugs with different sites of action. Shown are the predicted (solid line concentration addition, broken line independent action), and the observed (circles) cytotoxic effects on DU 145 prostate cancer cells. Doxorubicin, daunorubicin, vincristin, cis-platin, etoposide, melphalan and 5-fluorouracil were combined at equitoxic concentrations. The mixture effect predictions were derived from the concentration-response curves of the individual anticancer drugs...

Anthracydines have several modes of action leading to anticancer activity. They intercalate between base pairs in DNA, interfering with nucleic acid synthesis. Anthracydines also inhibit DNA topoisomerases I and II, which leads to DNA double-strand breaks. In addition, doxorubicin and daunorubicin may form complexes with metals such as iron. Although these metal-anthracycline complexes result in oxygen free radical formation, which may contribute to antitumor activity, membrane damage incurred from the free radicals is thought to be the mechanism responsible for... 

The imxle.s of action of doxorubicin arc similar tu those (ka>ciibcd for daunorubicin. 

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. 

Daunorubicin (1) is a particularly efficient agent in the treatment of acute myelocytic and lymphocytic leukemia. Doxorubicin (2) exhibits a broader spectrum of action, including many solid tumors, and is currently used in the control of breast, ovary, thyroid and lung carcinoma as well as in the treatment of several blood cancers [6],... 

Describe the mechanism of action of anthracycline antineoplastics (e.g., daunorubicin). 

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 - SO hours. All anthracyclines are converted to an active alcohol intermediate that plays a variable role in their therapeutic activity. Idarubicin has a tj of 15 hours, and its active metabolite, idarubicinol, has a tj of - 40 hours. There is rapid upt e 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 idarubicinol, 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. 

A considerable amount of research has gone into elucidating the molecular mechanism of action of these antitumour quinones. While several mechanisms are possible, a single mechanism may not fully explain all of the observed cytotoxic effects. One of the objectives of the NCI and other studies elsewhere has been to determine if there were any structure-activity relationships within the major structural groups ranging from the simplest benzoquinones to the complex multiple heteroatom quinones. One of the main conclusions from these studies was that the most active compounds were mitomycin C, the 3,6-diaziridinylbenzoquinones with 2,5-alkylamino substituents, adriamycin (doxorubicin), daunomycin (daunorubicin) and AZQ (Figure 1). 

The mechanism of action of dactiromycin and daunorubicin will be dealt with individually as... 

Boucek and colleagues (1993) examined the effect of doxorubicin on the SR function in isolated intact and permeabilized rabbit cardiac tissue. In the latter study, it was noted that doxorubicin (10-120 pM) was able to cause contractions in a similar manner to caffeine by releasing Ca " from SR and seemed to have no impact on the function of the myofilaments. Evidence has also been presented to indicate that anthracyclines (daunorubicin 10-300 pM) can perturb Ca " handling by the SR in a free radical-independent manner in rabbit cardiac tissue however, the quinone moiety of the molecule appears to be a prerequisite for such an action (Shadle et al. 2000). It is possible that alterations in Ca " release from the SR by anthracyclines could contribute to the inotropic and lusitropic dysfunction observed in cardiac tissue with this class of drugs. 

Doxorubicin (4,27) (adriamycin), and the related daunorubicin, are much used clinically in the treatment of solid tumours and leukaemias respectively. They are strong intercalators and act as cations thanks to the amino-group attached to the carbohydrate moiety. However, their mode of action is not fully understood and they have been placed in Section 4.0.4 with drugs that destroy DNA. 

The source of ptopionyl-SCoA in daunorubicin- and doxorubicin-producing screp-lomyceres is not known. In other organisms in which (wopionyl-SCoA is an important precursor for antibiotic biosynthesis, it is derived via, at least, the catabolism of valine through the action oft-valine dehydrogenase (319). 

Tsuchiya T, Takagi Y. Synthesis and biological activities of fluorinated daunorubicin and doxonibicin analogues. Pricbe W, ed. Anthracycline Antibiotics New Analt ues. Methods of Delivery, and Mechanisms of Action. Washington D.C. American Oiemical Society Press, 1995 100-114. 

Nous avons presente trois applications de la radiolyse pulsee a 1 etude du mode d action de medicaments antitumoraux. Nous avons pu caracteriser les intermediaires formes par trans-fert monoelectronique et nous avons mis en evidence plusieuurs reactions qui peuvent intervenir in vivo comme la capture des radicaux libres O par la forme radicalaire oxydee du BD 40, la possibilite pour la daunorubicine de capter les electrons quand elle est intercalee dans une proteine. Enfin nous avons isole la forme active de la mitomycine C responsable de son action sur I ADN. La methode de la radiolyse pulsee a permis I e-tude cinetique quantitative et systematique de telles reactions. 

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