Topoisomerase II; Daunorubicins/Doxorubicins

Daunorubicin (intravenous injection, 3 mg/kg, three times at 48 h intervals.) causes nephrotoxicity and cardiotoxicity in rats[5]. Daunorubicin (intraperitoneal injection, 10 mg/kg) causes sister chromatid exchanges in mice[7].

Daunorubicin inhibits of both DNA and RNA syntheses in HeLa cells over a concentration range of 0.2 through 2 μM.

Daunorubicin significantly inhibits the biosynthesis of DNA and RNA macromolecules when administered to leukemic cells isolated from patients with acute lymphocytic leukemia.

Absorption, Distribution and Excretion
Daunorubicin was found to have a tmax of 2 h and a cmax of 24.8 μg/mL after a 90 min infusion of the liposomal formulation at a dose of 44 mg/m2.
Daunorubicin is eliminated hepatically. 40% of daunorubicin is excreted in the bile while 25% is excreted in an active form (daunorubicin or daunorubicinol) in the urine. In the liposomal formulation, only 9% of active molecules are excreted in the urine.
Daunorubicin has a steady-state volume of distribution of 1.91 L/m² reported with the liposomal formulation. The average volume of distribution reported for the liposomal formulation is 6.6 L.
Daunorubicin has a clearance of 68.4 mL/h/m² determined using the liposomal formulation.
Note: Liposomal encapsulation can substantially affect a drug's functional properties relative to those of the unencapsulated drug. In addition, different liposomal drug products may vary from one another in the chemical composition and physical form of the liposomes. Such differences can substantially affect the functional properties of liposomal drug products.
Encapsulation of daunorubicin citrate in liposomes substantially alters the pharmacokinetics of the drug relative to conventional iv formulations (ie, nonencapsulated drug) with resultant decreased distribution into the peripheral compartment, increased distribution into Kaposi's lesions, and decreased plasma clearance
Daunorubicin hydrochloride is extremely irritating to tissues and, therefore, must be administered iv. Following iv infusion of a single 40-mg/sq m dose of liposomal daunorubicin citrate as a liposomal injection in patients with AIDS-related Kaposi's sarcoma, mean peak plasma daunorubicin (mostly bound to liposomes) concentrations are approximately 18 mug/mL following a 30-60 minute infusion. Peak plasma concentrations of daunorubicin are higher following iv administration of liposomal daunorubicin citrate than those attained following iv administration of conventional (nonencapsulated) daunorubicin hydrochloride.
In one study in patients with disseminated malignancies receiving a single 80-mg/sq m iv dose of nonencapsulated daunorubicin, peak plasma concentrations of the drug were 0.4 ug/mL while in patients with solid tumors (including those with Kaposi's sarcoma) who received a single 80-mg/sq m iv dose of liposomal daunorubicin, peak plasma concentrations of daunorubicin were about 44 ug/mL (about 100-fold greater than those receiving a comparable dose of the nonencapsulated drug); area under the plasma concentration-time curve (AUC) was about 36-fold greater than that observed with conventional daunorubicin hydrochloride. Following iv administration of liposomal daunorubicin, peak plasma concentrations and AUCs of daunorubicin generally increase linearly with increasing doses (at doses of 10-80 ug/mL).
For more Absorption, Distribution and Excretion (Complete) data for DAUNORUBICIN (18 total), please visit the HSDB record page.

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Metabolism / Metabolites
Daunorubicin hydrochloride is extensively metabolized in the liver and other tissues, mainly by cytoplasmic aldo-keto reductases, producing daunorubicinol, the major metabolite which has antineoplastic activity. Approximately 40% of the drug in the plasma is present as daunorubicinol within 30 minutes and 60% in 4 hours after a dose of nonencapsulated daunorubicin.
Daunorubicinol has been detected only in low concentrations in the plasma following iv administration of daunorubicin citrate liposomal injection. In patients with AIDS-associated Kaposi's sarcoma receiving iv administration of liposomal daunorubicin doses of 40 mg/sq m, the AUC of daunorubicinol represented only 2% of the total daunorubicin AUC. Additional metabolism by reductive cleavage of the glycosidic bond produces aglycones, which have little or no cytotoxic activity and are demethylated and conjugated with sulfate and glucuronide by microsomal enzymes.
Metabolites identified in human urine are daunorubicinol, daunorubicinol aglycone, desmethyldeoxydaunorubicinol aglycone, desmethyldeoxyrubicinol aglycone-4-o-sulfate, desmethyloxydaunorubicinol aglycone-4-o-glucuronide, and deoxydaunorubicinol aglycone glucuronide.
Extensively metabolized, initially to active alcohol metabolites; further metabolized by liver microsomes to inactive aglycones and demethylated glucuronide and sulfate conjugates.
Hepatic
Route of Elimination: Twenty-five percent of an administered dose of daunorubicin hydrochloride is eliminated in an active form by urinary excretion and an estimated 40% by biliary excretion.
Half Life: 18.5 hours

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Biological Half-Life
Daunorubicin has been determined to have a terminal half-life of 18.5 h (+/- 4.9). Daunorubicinol, the primary active metabolite has been determined to have a terminal half-life of 26.7 h (+/- 12.8). The mean half-life of elimination of liposomal daunorubicin has been reported to be 22.1 h in pharmacokinetic studies and 31.5 h in official FDA labeling.
Following rapid iv administration of conventional daunorubicin hydrochloride injection, total plasma concentrations of daunorubicin and its metabolites decline in a triphasic manner, and plasma concentrations of unchanged daunorubicin decline in a biphasic manner.
The plasma half-life of nonencapsulated daunorubicin averages 45 minutes in the initial phase and 18.5 hours in the terminal phase. By 1 hour after administration of nonencapsulated daunorubicin, the predominant form of the drug in plasma is the active metabolite daunorubicinol, which has an average terminal plasma half-life of 26.7 hours.
The apparent elimination half-life of DaunoXome (daunorubicin citrate liposome injection) is 4.4 hours, far shorter than that of daunorubicin, and probably represents a distribution half-life.

Hepatotoxicity
Chemotherapy with daunorubicin in combination with other agents is associated with serum enzyme elevations in a proportion of patients depending upon the dose and other agents used. ALT elevations during daunorubicin therapy are usually asymptomatic and transient and may resolve without dose modification. In many instances, it is difficult to attribute the liver test abnormalities to daunorubicin, because of the exposure to other potentially hepatotoxic agents. There have been no convincing instances of acute, clinically apparent idiosyncratic liver injury with jaundice associated with daunorubicin therapy. However, high doses of daunorubicin given in combination with other antineoplastic agents have been linked to cases of sinusoidal obstruction syndrome, typically presenting with right upper quadrant pain 10 to 30 days after the infusion, followed by weight gain, ascites and liver test abnormalities. Fatalities due to hepatic failure have occurred, but most patients recover within 1 to 3 months of onset.
Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).

[1]. Activity of topoisomerase inhibitors daunorubicin, idarubicin, and aclarubicin in the Drosophila Somatic Mutation and Recombination Test. Environ Mol Mutagen. 2004;43(4):250-7.

[2]. Inhibition of DNA and RNA synthesis by daunorubicin in sensitive and resistant Ehrlich ascites tumor cells in vitro. Cancer Res. 1972 Jun;32(6):1307-14.

[3]. Melanin inhibits cytotoxic effects of Doxorubicin and Daunorubicin in MOLT 4 cells. Pigment Cell Res. 2003 Aug;16(4):351-4.

[4]. An effective in vitro antitumor response against human pancreatic carcinoma with paclitaxel and Daunorubicin by induction of both necrosis and apoptosis. Anticancer Res. 2004 Sep-Oct;24(5A):2617-26.

[5]. Telmisartan prevents the progression of renal injury in daunorubicin rats with the alteration of angiotensin II and endothelin-1 receptor expression associated with its PPAR-γ agonist actions. Toxicology. 2011 Jan 11;279(1-3):91-9.

[6]. MiR-15a-5p Confers Chemoresistance in Acute Myeloid Leukemia by Inhibiting Autophagy Induced by Daunorubicin. Int J Mol Sci. 2021 May 13;22(10):5153.

[7]. Doxorubicin suppresses chondrocyte differentiation by stimulating ROS production. Eur J Pharm Sci. 2021 Dec 1;167:106013.

Daunomycin can cause cancer according to an independent committee of scientific and health experts.
Anthracycline antibiotic. An anticancer agent.
Daunorubicin is a natural product found in Actinomadura roseola. It has a role as an antineoplastic agent and a bacterial metabolite. It is an anthracycline, a member of tetracenequinones, a member of p-quinones and an aminoglycoside antibiotic. It is a conjugate base of a daunorubicin(1+). It derives from a hydride of a tetracene.
A very toxic anthracycline aminoglycoside antineoplastic isolated from Streptomyces peucetius and others, used in treatment of leukemia and other neoplasms.
Daunorubicin is an Anthracycline Topoisomerase Inhibitor. The mechanism of action of daunorubicin is as a Topoisomerase Inhibitor.
Daunorubicin is an anthracycline antibiotic that has antineoplastic activity and is used in the therapy of acute leukemia and AIDS related Kaposi sarcoma. Daunorubicin is associated with a low rate of transient serum enzyme and bilirubin elevations during therapy, but has not been implicated in cases of clinically apparent acute liver injury with jaundice.
Daunorubicin has been reported in Streptomyces, Brassica napus, and other organisms with data available.
Daunorubicin is an anthracycline antineoplastic antibiotic with therapeutic effects similar to those of doxorubicin. Daunorubicin exhibits cytotoxic activity through topoisomerase-mediated interaction with DNA, thereby inhibiting DNA replication and repair and RNA and protein synthesis.
Daunorubicin is only found in individuals that have used or taken this drug. It is a very toxic anthracycline aminoglycoside antineoplastic isolated from Streptomyces peucetius and others, used in treatment of leukemia and other neoplasms. [PubChem]Daunorubicin has antimitotic and cytotoxic activity through a number of proposed mechanisms of action: Daunorubicin forms complexes with DNA by intercalation between base pairs, and it inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes.
A very toxic anthracycline aminoglycoside antineoplastic isolated from Streptomyces peucetius and others, used in treatment of LEUKEMIA and other NEOPLASMS.
See also: Daunorubicin Hydrochloride (annotation moved to).

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Drug Indication
For remission induction in acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid) of adults and for remission induction in acute lymphocytic leukemia of children and adults. Daunorubicin is indicated in combination with [cytarabine] for the treatment of newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC) in adults and pediatric patients 1 year and older.

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Mechanism of Action
Daunorubicin has antimitotic and cytotoxic activity through a number of proposed mechanisms of action: Daunorubicin forms complexes with DNA by intercalation between base pairs, and it inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes.
Daunorubicin is an antineoplastic antibiotic. Daunorubicin has antimitotic and cytotoxic activity. Daunorubicin forms a complex with DNA by intercalation between base pairs. By stabilizing the complex between DNA and topoisomerase II, daunorubicin inhibits the activity of this enzyme, resulting in single-strand and double-strand breaks in DNA. Daunorubicin also may inhibit polymerase activity, affect regulation of gene expression, and be involved in free radical damage to DNA. Although daunorubicin is maximally cytotoxic in the S phase, the drug is not cycle-phase specific. Daunorubicin also has antibacterial and immunosuppressive properties.
Anthracyclines are an important reagent in many chemotherapy regimes for treating a wide range of tumors. One of the primary mechanisms of anthracycline action involves DNA damage caused by inhibition of topoisomerase II. Enzymatic detoxification of anthracycline is a major critical factor that determines anthracycline resistance. Natural product, daunorubicin a toxic analogue of anthracycline is reduced to less toxic daunorubicinol by the AKR1B10, enzyme, which is overexpressed in most cases of smoking associate squamous cell carcinoma (SCC) and adenocarcinoma. In addition, AKR1B10 was discovered as an enzyme overexpressed in human liver, cervical and endometrial cancer cases in samples from uterine cancer patients. Also, the expression of AKR1B10 was associated with tumor recurrence after surgery and keratinization of squamous cell carcinoma in cervical cancer and estimated to have the potential as a tumor intervention target colorectal cancer cells (HCT-8) and diagnostic marker for non-small-cell lung cancer. This article presents the mechanism of daunorubicin action and a method to improve the effectiveness of daunorubicin by modulating the activity of AKR1B10.
... In the present study using the ATP depleting agents cyanide, azide, or dinitrophenol to inhibit energy dependent transport processes, /investigators/ observed even larger increases in daunorubicin accumulation than were seen with CsA. Similar patterns were seen in a wide range of P-gp negative human cancer cell lines. Also the observed cyanide effect did not correlate with the expression of mRNA for multidrug resistance-associated protein (MRP), the only other member of the ABC family of membrane transporters that is known to be capable of effluxing daunorubicin. Thse results suggest that daunorubicin accumulation in many cases of AML is modulated by one or more novel energy-dependent processes that are distinct from P-gp or MRP. /The authors/ speculate that this novel drug transport mechanism(s) may influence the response of AML patients to daunorubicin and other therapeutic agents.
Inhibits DNA synthesis and blocks DNA-directed RNA polymerase. It can prevent cell division in doses that do not interfere with nucleic acid synthesis.

C27H29NO10

527.53

527.179

C, 61.48; H, 5.54; N, 2.66; O, 30.33

20830-81-3

30323

Dark Red Solid powder

1.6±0.1 g/cm3

770.0±60.0 °C at 760 mmHg

155ºC

419.5±32.9 °C

0.0±2.8 mmHg at 25°C

1.692

2.92

5

11

4

38

960

6

O=C(C(C(OC)=CC=C1)=C1C2=O)C3=C2C(O)=C(C[C@@](O)(C(C)=O)C[C@@H]4O[C@@]5([H])C[C@H](N)[C@H](O)[C@H](C)O5)C4=C3O

STQGQHZAVUOBTE-VGBVRHCVSA-N

InChI=1S/C27H29NO10/c1-10-22(30)14(28)7-17(37-10)38-16-9-27(35,11(2)29)8-13-19(16)26(34)21-20(24(13)32)23(31)12-5-4-6-15(36-3)18(12)25(21)33/h4-6,10,14,16-17,22,30,32,34-35H,7-9,28H2,1-3H3/t10-,14-,16-,17-,22+,27-/m0/s1

(7S,9S)-9-acetyl-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione

Daunomycin HCl; RP 13057; Rubidomycin; RP-13057; RP13057; Daunomycin hydrochloride; daunomycin HCl; daunorubidomycine; US brand names: Cerubidine; Rubidomycin; Foreign brand names: Cerubidin; Daunoblastin; Daunoblastina; Ondena; Rubilem; Abbreviations: DNM; DNR; DRB; Code names: FI6339; RP13057

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)