Daunorubicin

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Daunorubicin
Daunorubicin2DACS.svg
Daunorubicin ball-and-stick.png
Clinical data
Trade names Cerubidine, others
AHFS/Drugs.com Monograph
MedlinePlus a682289
Pregnancy
category
Routes of
administration
Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Metabolism Liver
Elimination half-life 26.7 hours (metabolite)
Excretion Bile duct and urinary
Identifiers
  • (8S,10S)-8-Acetyl-10-[(2S,4S,5S,6S)-
    4-amino-5-hydroxy-6-methyl-oxan-
    2-yl]oxy-6,8,11-trihydroxy-1-methoxy-
    9,10-dihydro-7H-tetracene-5,12-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.040.048 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C27H29NO10
Molar mass 527.526 g·mol−1
3D model (JSmol)
  • C[C@H]1[C@H]([C@H](C[C@@H](O1)O[C@H]2C[C@@](Cc3c2c(c4c(c3O)C(=O)c5cccc(c5C4=O)OC)O)(C(=O)C)O)N)O
  • 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 Yes check.svgY
  • Key:STQGQHZAVUOBTE-VGBVRHCVSA-N Yes check.svgY
   (verify)

Daunorubicin, also known as daunomycin, is a chemotherapy medication used to treat cancer. [2] Specifically it is used for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and Kaposi's sarcoma. [2] It is administered by injection into a vein. [2] A liposomal formulation known as liposomal daunorubicin also exists. [2]

Contents

Common side effects include hair loss, vomiting, bone marrow suppression, and inflammation of the inside of the mouth. [2] Other severe side effects include heart disease and tissue death at the site of injection. [2] Use in pregnancy may harm the fetus. [2] Daunorubicin is in the anthracycline family of medication. [3] It works in part by blocking the function of topoisomerase II. [2]

Daunorubicin was approved for medical use in the United States in 1979. [2] It is on the World Health Organization's List of Essential Medicines. [4] It was originally isolated from bacteria of the Streptomyces type. [5]

Medical uses

It slows or stops the growth of cancer cells in the body. Treatment is usually performed together with other chemotherapy drugs (such as cytarabine), and its administration depends on the type of tumor and the degree of response.[ citation needed ]

In addition to its major use in treating acute myeloid leukemia, daunorubicin is also used to treat neuroblastoma. Daunorubicin has been used with other chemotherapy agents to treat the blastic phase of chronic myelogenous leukemia.[ citation needed ]

Daunorubicin is also used as the starting material for semi-synthetic manufacturing of doxorubicin, epirubicin and idarubicin.[ citation needed ]

Mechanism of action

Similar to doxorubicin, daunorubicin interacts with DNA by intercalation and inhibition of macromolecular biosynthesis. [6] [7] This inhibits the progression of the enzyme topoisomerase II, which relaxes supercoils in DNA; without action of topoisomerase II, these DNA supercoils interfere in transcription of DNA. Daunorubicin stabilizes the topoisomerase II complex after it has broken the DNA chain for replication, preventing the DNA double helix from being resealed and thereby stopping the process of replication. On binding to DNA, daunomycin intercalates, with its daunosamine residue directed toward the minor groove. It has the highest preference for two adjacent G/C base pairs flanked on the 5' side by an A/T base pair. Crystallography shows that daunomycin induces a local unwinding angle of 8°, and other conformational disturbances of adjacent and second-neighbour base pairs. [8] It can also induce histone eviction from chromatin upon intercalation. [9] [10]

History

In the 1950s, an Italian research company, Farmitalia Research Laboratories, began an organized effort to isolate anticancer compounds from soil-based microbes. A soil sample was isolated from the area surrounding the Castel del Monte, a 13th-century castle in Apulia. A new strain of Streptomyces peucetius which produced a red pigment was isolated, and an antibiotic was produced from this bacterium that was found to have good activity against murine tumors. Since a group of French researchers discovered the same compound at about the same time, the two teams named the compound daunorubicin, combining the name Dauni , a pre-Roman tribe that occupied the area of Italy where the compound was isolated, with the French word for ruby, rubis, describing the color. [11] [12] [13] Clinical trials began in the 1960s, and the drug saw success in treating acute leukemia and lymphoma.

However, by 1967, it was recognized that daunorubicin could produce fatal cardiac toxicity. [14]

In 2015–16, a team at Ohio State University "showed that, by carefully manipulating strands of viral DNA, an origami structure with complex folds can be created in just 10 minutes. Incredibly, these structures are only 100 nanometers across – that’s 1,000 times smaller than the width of a human hair. Small volumes of daunorubicin can be wrapped up in these minuscule pods, which can then be released into a leukemia cell-filled environment." [15] [16] [ unreliable medical source? ]

Route of administration

Daunorubicin should only be administered in a rapid intravenous infusion. It should not be administered intramuscularly or subcutaneously, since it may cause extensive tissue necrosis. It should also never be administered intrathecally (into the spinal canal), as this will cause extensive damage to the nervous system and may lead to death. Daunorubicin has been used intravitreally (inside the eye) for the purposes of preventing proliferative vitreoretinopathy, a common complication following retinal detachment surgery, but has not been found to be effective and is not used for any other ophthalmic purposes at this time. [17]

Related Research Articles

<span class="mw-page-title-main">Chemotherapy</span> Treatment of cancer using drugs that inhibit cell division or kill cells

Chemotherapy is the type of cancer treatment that uses one or more anti-cancer drugs in a standard regimen. Chemotherapy may be given with a curative intent, or it may aim only to prolong life or to reduce symptoms. Chemotherapy is one of the major categories of the medical discipline specifically devoted to pharmacotherapy for cancer, which is called medical oncology.

DNA topoisomerases are enzymes that catalyze changes in the topological state of DNA, interconverting relaxed and supercoiled forms, linked (catenated) and unlinked species, and knotted and unknotted DNA. Topological issues in DNA arise due to the intertwined nature of its double-helical structure, which, for example, can lead to overwinding of the DNA duplex during DNA replication and transcription. If left unchanged, this torsion would eventually stop the DNA or RNA polymerases involved in these processes from continuing along the DNA helix. A second topological challenge results from the linking or tangling of DNA during replication. Left unresolved, links between replicated DNA will impede cell division. The DNA topoisomerases prevent and correct these types of topological problems. They do this by binding to DNA and cutting the sugar-phosphate backbone of either one or both of the DNA strands. This transient break allows the DNA to be untangled or unwound, and, at the end of these processes, the DNA backbone is resealed. Since the overall chemical composition and connectivity of the DNA do not change, the DNA substrate and product are chemical isomers, differing only in their topology.

<span class="mw-page-title-main">Cytarabine</span> Chemical compound (chemotherapy medication)

Cytarabine, also known as cytosine arabinoside (ara-C), is a chemotherapy medication used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and non-Hodgkin's lymphoma. It is given by injection into a vein, under the skin, or into the cerebrospinal fluid. There is a liposomal formulation for which there is tentative evidence of better outcomes in lymphoma involving the meninges.

<span class="mw-page-title-main">Idarubicin</span> Anthracycline antileukemic drug

Idarubicin or 4-demethoxydaunorubicin is an anthracycline antileukemic drug. It inserts itself into DNA and prevents DNA unwinding by interfering with the enzyme topoisomerase II. It is an analog of daunorubicin, but the absence of a methoxy group increases its fat solubility and cellular uptake. Similar to other anthracyclines, it also induces histone eviction from chromatin.

<span class="mw-page-title-main">Doxorubicin</span> Chemotherapy medication

Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used together with other chemotherapy agents. Doxorubicin is given by injection into a vein.

<span class="mw-page-title-main">Antimetabolite</span> Chemical that inhibits the use of a metabolite

An antimetabolite is a chemical that inhibits the use of a metabolite, which is another chemical that is part of normal metabolism. Such substances are often similar in structure to the metabolite that they interfere with, such as the antifolates that interfere with the use of folic acid; thus, competitive inhibition can occur, and the presence of antimetabolites can have toxic effects on cells, such as halting cell growth and cell division, so these compounds are used in chemotherapy for cancer.

<span class="mw-page-title-main">History of cancer chemotherapy</span>

The era of cancer chemotherapy began in the 1940s with the first use of nitrogen mustards and folic acid antagonist drugs. The targeted therapy revolution has arrived, but many of the principles and limitations of chemotherapy discovered by the early researchers still apply.

<span class="mw-page-title-main">Anthracycline</span> Class of antibiotics

Anthracyclines are a class of drugs used in cancer chemotherapy that are extracted from Streptomyces bacterium. These compounds are used to treat many cancers, including leukemias, lymphomas, breast, stomach, uterine, ovarian, bladder cancer, and lung cancers. The first anthracycline discovered was daunorubicin, which is produced naturally by Streptomyces peucetius, a species of Actinomycetota. Clinically the most important anthracyclines are doxorubicin, daunorubicin, epirubicin and idarubicin.

<span class="mw-page-title-main">Epirubicin</span> Chemical compound

Epirubicin is an anthracycline drug used for chemotherapy. It can be used in combination with other medications to treat breast cancer in patients who have had surgery to remove the tumor. It is marketed by Pfizer under the trade name Ellence in the US and Pharmorubicin or Epirubicin Ebewe elsewhere.

<span class="mw-page-title-main">Etoposide</span> Chemotherapy medication

Etoposide, sold under the brand name Vepesid among others, is a chemotherapy medication used for the treatments of a number of types of cancer including testicular cancer, lung cancer, lymphoma, leukemia, neuroblastoma, and ovarian cancer. It is also used for hemophagocytic lymphohistiocytosis. It is used by mouth or injection into a vein.

<span class="mw-page-title-main">Dexrazoxane</span> Chemical compound

Dexrazoxane hydrochloride is a cardioprotective agent. It was discovered by Eugene Herman in 1972. The IV administration of dexrazoxane is in acidic condition with HCl adjusting the pH.

<span class="mw-page-title-main">Amsacrine</span> Chemical compound

Amsacrine is an antineoplastic agent.

Topoisomerase inhibitors are chemical compounds that block the action of topoisomerases, which are broken into two broad subtypes: type I topoisomerases (TopI) and type II topoisomerases (TopII). Topoisomerase plays important roles in cellular reproduction and DNA organization, as they mediate the cleavage of single and double stranded DNA to relax supercoils, untangle catenanes, and condense chromosomes in eukaryotic cells. Topoisomerase inhibitors influence these essential cellular processes. Some topoisomerase inhibitors prevent topoisomerases from performing DNA strand breaks while others, deemed topoisomerase poisons, associate with topoisomerase-DNA complexes and prevent the re-ligation step of the topoisomerase mechanism. These topoisomerase-DNA-inhibitor complexes are cytotoxic agents, as the un-repaired single- and double stranded DNA breaks they cause can lead to apoptosis and cell death. Because of this ability to induce apoptosis, topoisomerase inhibitors have gained interest as therapeutics against infectious and cancerous cells.

<span class="mw-page-title-main">Pixantrone</span> Chemical compound

Pixantrone is an experimental antineoplastic (anti-cancer) drug, an analogue of mitoxantrone with fewer toxic effects on cardiac tissue. It acts as a topoisomerase II poison and intercalating agent. The code name BBR 2778 refers to pixantrone dimaleate, the actual substance commonly used in clinical trials.

<span class="mw-page-title-main">Aclarubicin</span> Chemical compound

Aclarubicin (INN) or aclacinomycin A is an anthracycline drug that is used in the treatment of cancer in China. It was previously approved for use in Europe but was discontinued in 2004 due to being rarely prescribed and unprofitable.

"7+3" in the context of chemotherapy is an acronym for a chemotherapy regimen that is most often used today as first-line induction therapy in acute myelogenous leukemia, excluding the acute promyelocytic leukemia form, which is better treated with ATRA and/or arsenic trioxide and requires less chemotherapy.

ADE is a chemotherapy regimen most often used as an induction or consolidation regimen in acute myelogenous leukemia, especially in poor-risk patients or those refractory to the standard first-line induction with standard "7+3" regimen or who are relapsed after the standard chemotherapy.

DAT in the context of chemotherapy is an acronym that means a chemotherapy regimen most often used as an induction regimen in acute myelogenous leukemia, usually for those who are refractory to the standard "7+3" induction regimen or who has relapsed. But this regimen also can be used as primary, first-line induction therapy.

<span class="mw-page-title-main">Daunorubicin/cytarabine</span> Pharmaceutical drug

Daunorubicin/cytarabine, sold under the brand name Vyxeos, is a fixed-dose combination medication used for the treatment of acute myeloid leukemia. It contains the liposomal bound daunorubicin, an anthracycline topoisomerase inhibitor, and cytarabine, a nucleoside metabolic inhibitor.

<span class="mw-page-title-main">Bisantrene</span> Chemical compound

Bisantrene is an anthracenyl bishydrazone with anthracycline-like antineoplastic activity and an antimetabolite. Bisantrene intercalates with and disrupts the configuration of DNA, resulting in DNA single-strand breaks, DNA-protein crosslinking, and inhibition of DNA replication. This agent is similar to doxorubicin in chemotherapeutic activity, but unlike anthracyclines like doxorubicin, it exhibits little cardiotoxicity.

References

  1. "Daunorubicin (Cerubidine) Use During Pregnancy". Drugs.com. 19 September 2019. Retrieved 15 August 2020.
  2. 1 2 3 4 5 6 7 8 9 "Daunorubicin hydrochloride". The American Society of Health-System Pharmacists. Archived from the original on 8 January 2017. Retrieved 8 December 2016.
  3. British National Formulary: BNF 69 (69th ed.). British Medical Association. 2015. pp. 581–583. ISBN   9780857111562.
  4. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
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  7. Momparler RL, Karon M, Siegel SE, Avila F (August 1976). "Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells". Cancer Research. 36 (8): 2891–2895. PMID   1277199. Archived from the original on 5 February 2009.
  8. Quigley GJ, Wang AH, Ughetto G, van der Marel G, van Boom JH, Rich A (December 1980). "Molecular structure of an anticancer drug-DNA complex: daunomycin plus d(CpGpTpApCpG)". Proceedings of the National Academy of Sciences of the United States of America. 77 (12): 7204–7208. Bibcode:1980PNAS...77.7204Q. doi: 10.1073/pnas.77.12.7204 . PMC   350470 . PMID   6938965.
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  12. Baruffa G (1966). "Clinical trials in Plasmodium falciparum malaria with a long-acting sulphonamide". Transactions of the Royal Society of Tropical Medicine and Hygiene. 60 (2): 222–224. doi:10.1016/0035-9203(66)90030-7. PMID   5332105.
  13. Camerino B, Palamidessi G (1960). "Derivati della parazina II. Sulfonamdopir" [Derivatives of parazine II. Sulfonamdopir]. Gazzetta Chimica Italiana[Italian Chemical Journal] (in Italian). 90: 1802–1815.
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  15. "Researchers kill drug-resistant leukemia cells using DNA Trojan horse attack". IFL Science. 25 February 2016.
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  17. Mortensen ME, Cecalupo AJ, Lo WD, Egorin MJ, Batley R (1992). "Inadvertent intrathecal injection of daunorubicin with fatal outcome". Medical and Pediatric Oncology. 20 (3): 249–253. doi:10.1002/mpo.2950200315. PMID   1574039.