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Doxorubicin
Systematic (IUPAC) name
(8S,10S)-10-(4-amino-5-hydroxy-6-methyl-
tetrahydro-2H-pyran-2-yloxy)
-6,8,11-trihydroxy-8-(2-hydroxyacetyl)
-1-methoxy-7,8,9,10-tetrahydrotetracene
-5,12-dione
Identifiers
CAS number 23214-92-8
ATC code L01DB01
PubChem 31703
DrugBank APRD00185
Chemical data
Formula C27H29NO11 
Mol. mass 543. IUPAC Nomenclature is a system of naming Chemical compounds and of describing the science of Chemistry in general CAS registry numbers are unique numerical identifiers for Chemical compounds Polymers biological sequences mixtures and Alloys They are also referred to The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs It is controlled by the WHO Collaborating Centre for Drug A section of the Anatomical Therapeutic Chemical Classification System. PubChem is a Database of chemical Molecules The system is maintained by the National Center for Biotechnology Information (NCBI a component The DrugBank database available at the University of Alberta is a unique Bioinformatics and Cheminformatics resource that combines detailed drug (i A chemical formula is a way of expressing information about the Atoms that constitute a particular Chemical compound, and how the relationship between those atoms changes Carbon (kɑɹbən is a Chemical element with the symbol C and its Atomic number is 6 Hydrogen (ˈhaɪdrədʒən is the Chemical element with Atomic number 1 Nitrogen (ˈnaɪtɹəʤɪn is a Chemical element that has the symbol N and Atomic number 7 and Atomic weight 14 Oxygen (from the Greek roots ὀξύς (oxys (acid literally "sharp" from the taste of acids and -γενής (-genēs (producer literally begetteris the The molecular mass (abbreviated m of a substance, more commonly referred to as molecular weight and abbreviated as MW, is the Mass of one 52 g/mol
Pharmacokinetic data
Bioavailability 5% (Oral)
Metabolism CYP3A4
Half life 12-18. For other uses of the words gram or gramme see Gram (disambiguation. The mole (symbol mol) is a unit of Amount of substance: it is an SI base unit, and almost the only unit to be used to measure this In Pharmacology, bioavailability is used to describe the fraction of an administered Dose of unchanged drug that reaches the Systemic circulation, one of Drug metabolism is the Metabolism of drugs, their Biochemical modification or degradation usually through specialized enzymatic systems Cytochrome P450 3A4 (abbreviated CYP3A4) ( a member of the Cytochrome P450 mixed-function oxidase system is one of the most important enzymes involved in the metabolism The biological half-life of a substance is the time it takes for a substance (drug radioactive nuclide or other to lose half of its pharmacologic physiologic or radiologic activity 5 hours[1]
Excretion Biliary and fecal
Therapeutic considerations
Pregnancy cat.

D(AU) D(US)
Legal status

POM(UK) ℞-only(US)
Routes Intravenous

Doxorubicin (trade name Adriamycin) or hydroxyldaunorubicin is a drug widely used in cancer chemotherapy. Excretion is the process of eliminating waste products of Metabolism and other non-useful materials The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical if it is used as directed by the mother during For a topic outline on this subject see List of basic Australia topics. The United States of America —commonly referred to as the The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction A prescription drug is a licensed medicine that is regulated by legislation to require a prescription before it can be obtained The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom, the UK or Britain,is a Sovereign state located A prescription drug is a licensed medicine that is regulated by legislation to require a prescription before it can be obtained The United States of America —commonly referred to as the In Pharmacology and Toxicology, a route Intravenous therapy or IV therapy is the giving of Liquid substances directly into a Vein. Chemotherapy, in its most general sense refers to treatment of disease by chemicals that kill cells specifically those of micro-organisms or Cancer. It is an anthracycline antibiotic and structurally closely related to daunomycin, and also intercalates DNA. Anthracyclines (or anthracycline antibiotics) are a class of drugs used in cancer chemotherapy. In modern usage an antibiotic is a Chemotherapeutic agent with activity against Microorganisms such as Bacteria, fungi or Protozoa Daunorubicin or daunomycin (daunomycin cerubidine is Chemotherapy of the Anthracycline family that is given as a treatment for some types of Cancer In Chemistry, intercalation is the reversible inclusion of a Molecule (or group between two other molecules (or groups It is commonly used in the treatment of a wide range of cancers. Cancer (medical term Malignant Neoplasm) is a class of Diseases in which a group of cells display uncontrolled

The drug is administered by injection. It may be sold under the brand names Adriamycin PFS, Adriamycin RDF, or Rubex. [2] Doxil is a liposome-encapsulated dosage form of doxorubicin made by Ben Venue Laboratories for Johnson & Johnson. A liposome is a tiny bubble ( vesicle) made out of the same material as a cell membrane. Johnson & Johnson ( is a global American Pharmaceutical, Medical devices and consumer packaged goods Manufacturer founded in 1886 The main benefits of this form are a reduction in cardiotoxicity. It is photosensitive and it is often covered by an aluminium bag to prevent light interacting affecting it.

Contents

History

The history of doxorubicin can be traced back to the 1950s, when an Italian research company, Farmitalia Research Laboratories, began an organized effort to find anticancer compounds from soil-based microbes. Italy (Italia officially the Italian Republic, (Repubblica Italiana is located on the Italian Peninsula in Southern Europe, and on the two largest A microorganism (also spelled micro organism or micro-organism and also called a microbe) is an Organism that is Microscopic (usually A soil sample was isolated from the area surrounding the Castel del Monte, a 13th century castle. Castel del Monte can refer to Castel del Monte (Abruzzo, a commune and town in Province of L'Aquila, Abruzzo, Italy. A new strain of Streptomyces peucetius which produced a bright red pigment was isolated, and an antibiotic was produced from this bacterium that was found to have good activity against murine tumors. Streptomyces, the largest Genus of Actinobacteria and type genus of the family Streptomycetaceae. The Old World rats and mice, part of the Subfamily Murinae in the family Muridae, comprise at least 519 species 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. This article is about the country For a topic outline on this subject see List of basic France topics. Daunorubicin or daunomycin (daunomycin cerubidine is Chemotherapy of the Anthracycline family that is given as a treatment for some types of Cancer The Iapyges or Iapygians were an Indo-European people who inhabited the heel of Italy (modern Apulia) before being absorbed by the A Ruby is a pink to blood-red Gemstone, a variety of the Mineral Corundum ( Aluminium oxide) [3] 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. [4]

Researchers at Farmitalia soon discovered that changes in biological activity could be made by minor changes in the structure of the compound. A strain of Streptomyces was mutated using N-nitroso-N-methyl urethane and this new strain produced a different, red-colored antibiotic. They named this new compound Adriamycin, after the Adriatic Sea, and the name was later changed to doxorubicin to conform to the established naming convention. [5] Doxorubicin showed better activity than daunorubicin against murine tumors, and especially solid tumors. It also showed a relatively higher therapeutic index, yet the cardiotoxicity remained. Cardiotoxicity is the occurrence of heart muscle damage The heart becomes weaker and is not as efficient in pumping and therefore circulating blood [6]

Doxorubicin and daunorubicin together can be thought of as prototype compounds for the anthracyclines. A prototype is an original type form or instance of something serving as a typical example basis or standard for other things of the same category Subsequent research by many investigators throughout the world has led to many other anthracycline antibiotics, or analogs, and today, it is estimated that there are over 2,000 known analogs of doxorubicin. By 1991, 553 of them have been evaluated in the screening program at the National Cancer Institute (NCI). The National Cancer Institute (NCI is part of the United States Federal government's National Institutes of Health. [3]

Biosynthesis

Main article: Biosynthesis of doxorubicin

Doxorubicin (DXR) is a 14-hydroxylated version of daunorubicin, the immediate precursor of DXR in its biosynthetic pathway. Doxorubicin (DXR is a 14- Hydroxylated version of Daunorubicin, the immediate precursor of DXR in its biosynthetic pathway Hydroxylation is any chemical process that introduces one or more hydroxyl groups (-OH into a compound (or radical thereby oxidizing it Daunorubicin or daunomycin (daunomycin cerubidine is Chemotherapy of the Anthracycline family that is given as a treatment for some types of Cancer Biosynthesis is a phenomenon wherein Chemical compounds are produced from simpler Reagents Biosynthesis unlike Chemosynthesis, takes place within living Daunorubicin is more abundantly found as a natural product because it is produced by a number of different wild type strains of streptomyces. Daunorubicin or daunomycin (daunomycin cerubidine is Chemotherapy of the Anthracycline family that is given as a treatment for some types of Cancer A natural product is a Chemical compound or substance produced by a living organism - found in nature that usually has a pharmacological or biological activity for use in pharmaceutical Wild type, sometimes written wildtype or wild-type, is the typical form of an organism strain gene or characteristic as it occurs in nature In biology strain is a low-level Taxonomic rank used in three related ways Streptomyces, the largest Genus of Actinobacteria and type genus of the family Streptomycetaceae. In contrast, only one known non-wild type species, streptomyces peucetius subspecies cesius ATCC 27952, was initially found to be capable of producing the more widely used doxorubicin. Wild type, sometimes written wildtype or wild-type, is the typical form of an organism strain gene or characteristic as it occurs in nature In Biology, a species is one of the basic units of Biological classification and a Taxonomic rank. Streptomyces, the largest Genus of Actinobacteria and type genus of the family Streptomycetaceae. In Zoology, as in other branches of Biology, subspecies is the Taxonomic rank immediately subordinate to a Species. [7] This strain was created by Arcamone et. al in 1969 by mutating a strain producing daunorubicin, but not DXR, at least in detectable quantities. In biology mutations are changes to the Nucleotide sequence of the Genetic material of an organism In biology strain is a low-level Taxonomic rank used in three related ways [8] Subsequently, Hutchinson's group showed that under special environmental conditions, or by the introduction of genetic modifications, other strains of streptomyces can produce doxorubicin. In opposition to Mutations, modifications are included in the band width of the Genome of an individual creature [9] His group has also cloned many of the genes required for DXR production, although not all of them have been fully characterized. Cloning in Biology is the process of producing populations of genetically-identical individuals that occurs in nature when organisms such as Bacteria, Insects History See also History of genetics The existence of genes was first suggested by Gregor Mendel (1822-1884 who in the 1860s studied inheritance In 1996, Strohl's group discovered, isolated and characterized dox A, the gene encoding the enzyme that converts daunorubicin into DXR. History See also History of genetics The existence of genes was first suggested by Gregor Mendel (1822-1884 who in the 1860s studied inheritance Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins [10] By 1999, they produced recombinant Dox A, a Cytochrome P450 oxidase, and found that it catalyzes multiple steps in DXR biosynthesis, including steps leading to daunorubicin. Cytochrome P450 (abbreviated CYP, P450, infrequently CYP450) is a very large and diverse superfamily of Hemoproteins found in all Domains Catalysis is the process in which the rate of a Chemical reaction is increased by means of a Chemical substance known as a catalyst Biosynthesis is a phenomenon wherein Chemical compounds are produced from simpler Reagents Biosynthesis unlike Chemosynthesis, takes place within living [11] This was significant because it became clear that all daunorubicin producing strains have the necessary genes to produce DXR, the much more therapeutically important of the two. History See also History of genetics The existence of genes was first suggested by Gregor Mendel (1822-1884 who in the 1860s studied inheritance Hutchinson's group went on to develop methods to improve the yield of DXR, from the fermentation process used in its commercial production, not only by introducing Dox A encoding plasmids, but also by introducing mutations to deactivate enzymes that shunt DXR precursors to less useful products, for example baumycin-like glycosides. Fermentation has many important uses in industry Though the word fermentation can have stricter definitions when speaking of it in industrial fermentation it more loosely A plasmid is an extra-chromosomal DNA molecule separate from the chromosomal DNA which is capable of replicating independently of the chromosomal DNA Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins [7] Some triple mutants, that also over-expressed Dox A, were able to double the yield of DXR. Gene expression is the process by which inheritable information from a Gene, such as the DNA sequence, is made into a functional Gene product, such This is of more than academic interest because at that time DXR cost about $1. 37 million per kg and current production in 1999 was 225 kg per annum. [12] More efficient production techniques have brought the price down to $1. 1 million per kg for the non-liposomal formulation. A liposome is a tiny bubble ( vesicle) made out of the same material as a cell membrane. Although DXR can be produced semi-synthetically from daunorubicin, the process involves electrophilic bromination and multiple steps and the yield is poor. " Semisynthesis " or partial chemical synthesis is a type of Chemical synthesis that uses compounds isolated from Natural sources (e In Chemistry, an electrophile (literally electron-lover) is a Reagent attracted to Electrons that participates in a chemical reaction by accepting "Fluorination" redirects here For the addition of fluoride to drinking water see Water fluoridation. [13] Since daunorubicin is produced by fermentation, it would be ideal if the bacteria could complete DXR synthesis more effectively. Fermentation is the process of deriving energy from the oxidation of organic compounds such as carbohydrates using an endogenous electron acceptor which is The Bacteria ( singular: bacterium) are a large group of unicellular Microorganisms Typically a few Micrometres in length bacteria have

Cartoon diagram of two doxorubicin molecules intercalating DNA, from PDB 1D12.
Cartoon diagram of two doxorubicin molecules intercalating DNA, from PDB 1D12. The Protein Data Bank ( PDB) is a repository for 3-D structural data of Proteins and Nucleic acids These data typically obtained by X-ray crystallography

Mechanism of action

The exact mechanism of action of doxorubicin is complex and still somewhat unclear, though it is thought to interact with DNA by intercalation. Deoxyribonucleic acid ( DNA) is a Nucleic acid that contains the genetic instructions used in the development and functioning of all known [14] Doxorubicin is known to interact with DNA by intercalation and inhibition of macromolecular biosynthesis. In Chemistry, intercalation is the reversible inclusion of a Molecule (or group between two other molecules (or groups Biosynthesis is a phenomenon wherein Chemical compounds are produced from simpler Reagents Biosynthesis unlike Chemosynthesis, takes place within living [15] This inhibits the progression of the enzyme topoisomerase II, which unwinds DNA for transcription. Type II Topoisomerases cut both strands of the DNA helix simultaneously in order to change the Linking number of the molecule Transcription is the synthesis of RNA under the direction of DNA Doxorubicin 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. DNA replication is the process of copying a double-stranded DNA molecule to form two double-stranded molecules

The planar aromatic chromophore portion of the molecule intercalates between two base pairs of the DNA, while the six-membered daunosamine sugar sits in the minor groove and interacts with flanking base pairs immediately adjacent to the intercalation site, as evidenced by several crystal structures. [16][17]

Clinical use

Doxorubicin is commonly used to treat some leukemias, Hodgkin's lymphoma, as well as cancers of the bladder, breast, stomach, lung, ovaries, thyroid, soft tissue sarcoma, multiple myeloma, and others. Leukemia or leukaemia (Greek leukos λευκός, "white" aima αίμα, "blood" is a Cancer of the Blood Hodgkin's lymphoma, also known as Hodgkin's disease is a type of Lymphoma first described by Thomas Hodgkin in 1832 Bladder cancer refers to any of several types of malignant growths of the Urinary bladder. Breast cancer is a Cancer that starts in the cells of the Breast in women and men Stomach or gastric cancer can develop in any part of the Stomach and may spread throughout the stomach and to other organs particularly the Esophagus and Lung cancer is a Disease of uncontrolled Cell growth in tissues of the Lung. Ovarian cancer is a cancerous growth arising from an Ovary. The cancer most commonly forms in the lining of the ovary (resulting in epithelial Thyroid cancer refers to any of four kinds of malignant Tumors of the Thyroid gland papillary, follicular, medullary or A soft tissue sarcoma is a rare form of Cancer that develops in mesenchymal tissue the Muscle, Connective tissues and Bones of the body Multiple myeloma (also known as MM, myeloma, plasma cell myeloma, or as Kahler's disease after Otto Kahler) is a type of [2] Commonly used doxorubicin-containing regimens are CA (cyclophosphamide, Adriamycin), TAC (Taxotere, CA), ABVD (Adriamycin, Bleomycin, Vinblastine, Dacarbazine), CHOP (Cyclophosphamide, Adriamycin, Vincristine, Prednisone) and FAC (5-Fluorouracil, Adriamycin, Cyclophosphamide). Chemotherapy regimens are often identified with acronyms identifying the agents used in combination ABVD is a Chemotherapy regimen used in the first-line treatment of Hodgkin lymphoma. Bleomycin is a Glycopeptide antibiotic produced by the Bacterium Streptomyces verticillus. Vinblastine is an anti-mitotic drug used to treat certain kinds of Cancer, including Hodgkin's lymphoma, non-small cell Lung cancer Dacarbazine (da-KAR-ba-zeen (brand names DTIC DTIC-Dome also known as DIC or Imidazole Carboxamide is an antineoplastic Chemotherapy drug used in the treatment of various CHOP is the acronym for a Chemotherapy regimen used in the treatment of Non-Hodgkin lymphoma. Cyclophosphamide (the generic name for Cytoxan Neosar Revimmune also known as cytophosphane is a Nitrogen mustard alkylating agent, from the oxazophorines group Vincristine (brand name Oncovin also known as leurocristine, is a vinca Alkaloid from the Madagascar periwinkle ( Catharanthus roseus, Prednisone is a synthetic Corticosteroid drug that is usually taken orally but can be delivered by Intramuscular injection and can be used for a great number Doxil is used primarily for the treatment of ovarian cancer where the disease has progressed or recurred after platinum-based chemotherapy, or for the treatment of AIDS-related Kaposi's sarcoma. Platinum (ˈplætɪnəm is a Chemical element with the Atomic symbol Pt and an Atomic number of 78 Kaposi's sarcoma (KS is a tumor caused by Human herpesvirus 8 ( HHV8) also known as Kaposi's sarcoma-associated herpesvirus (KSHV [18]

Experimental therapy

Combination therapy experiments with sirolimus (rapamycin) and doxorubicin have shown promise in treating Akt-positive lymphomas in mice. In contemporary usage the expression combination therapy most often refers to the simultaneousadministration of two or more Medications to treat a single Disease, Sirolimus ( INN) is a relatively new immunosuppressant drug used to prevent rejection in organ transplantation, and is especially useful in Kidney Akt1, also known as "Akt" or Protein kinase B (PKB is an important molecule in mammalian cellular signaling Lymphoma a type of Neoplasm that originates in Lymphocytes (a type of White blood cell in the vertebrate Immune system) [19]

Recent animal research coupling a murine monoclonal antibody with doxorubicin has created an immunoconjugate that was able to eliminate HIV-1 infection in mice. The Old World rats and mice, part of the Subfamily Murinae in the family Muridae, comprise at least 519 species Monoclonal antibodies ( mAb or moAb) are monospecific antibodies that are identical because they are produced by one type of immune cell Immunoconjugates are antibodies conjugated to a second molecule usually a Toxin, Radioisotope or Label. Human immunodeficiency virus ( HIV) is a Lentivirus (a member of the Retrovirus family that can lead to acquired immunodeficiency syndrome Current treatment with antiretroviral therapy (ART) still leaves pockets of HIV within the host. The immunoconjugate could potentially provide a complimentary treatment to ART to eradicate antigen-expressing T cells. T cells belong to a group of White blood cells known as Lymphocytes, and play a central role in Cell-mediated immunity. [20]

Side effects

Acute side-effects of doxorubicin can include nausea, vomiting, and heart arrhythmias. Dysrhythmia redirects here For the American band see Dysrhythmia (band. It can also cause neutropenia (a decrease in white blood cells), as well as complete alopecia (hair loss). Neutropenia (adjective neutropenic) from Latin Prefix neutro- and Greek Suffix -πενία (deficiency is Alopecia or hair loss is the medical description of the loss of hair from the head or body sometimes to the extent of Baldness. When the cumulative dose of doxorubicin reaches 550 mg/m², the risks of developing cardiac side effects, including congestive heart failure, dilated cardiomyopathy, and death, dramatically increase. Heart failure is a Cardiac condition that occurs when a problem with the structure or function of the Heart impairs its ability to supply Cardiomyopathy, which literally means "heart muscle disease" is the deterioration of the function of the Myocardium (i Doxorubicin cardiotoxicity is characterized by a dose-dependent decline in mitochondrial oxidative phosphorylation. In Cell biology, a mitochondrion (plural mitochondria) is a membrane-enclosed Organelle found in most eukaryotic cells. Oxidative phosphorylation is a Metabolic pathway that uses energy released by the oxidation of Nutrients to produce Adenosine triphosphate (ATP Reactive oxygen species, generated by the interaction of doxorubicin with iron, can then damage the myocytes (heart cells), causing myofibrillar loss and cytoplasmic vacuolization. Additionally, some patients may develop Palmar plantar erythrodysesthesia, or, "Hand-Foot Syndrome," characterized by skin eruptions on the palms of the hand or soles of the feet, characterized by swelling, pain and erythema. Palmar plantar erythrodysesthesia (PPE is a swelling and numbness of the hands and feet that occurs with Chemotherapy, usually with Fluorouracil, Capecitabine [18]

Due to these side effects and its red color, doxorubicin has earned the nickname "red devil. " [21]

See also

References

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  19. ^ Wendel H, De Stanchina E, Fridman J, Malina A, Ray S, Kogan S, Cordon-Cardo C, Pelletier J, Lowe S (2004). "Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy". Nature 428 (6980): 332–7. Nature is a prominent Scientific journal, first published on 4 November 1869 doi:10.1038/nature02369. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 15029198.  
  20. ^ Johansson S, Goldenberg D, Griffiths G, Wahren B, Hinkula J (2006). "Elimination of HIV-1 infection by treatment with a doxorubicin-conjugated anti-envelope antibody. ". AIDS 20 (15): 1911-1915. doi:10.1097/01.aids.0000247111.58961.60. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 16988511.  
  21. ^ Bloch, Richard; Bloch, Annette. 25 Most Asked Questions. Fighting Cancer. R. A. Bloch Cancer Foundation. Retrieved on 2007-06-28. Year 2007 ( MMVII) was a Common year starting on Monday of the Gregorian calendar in the 21st century. Events 1098 - Fighters of the First Crusade defeat Kerbogha of Mosul.

External links

MedlinePlus, with the MedlinePlus Medical Encyclopedia, is a website network containing Health information from the world's largest medical Library

Dictionary

doxorubicin

-noun

  1. A particular drug used in chemotherapy.
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