|
|
| Line 1: |
Line 1: |
| {{Drugbox
| | #REDIRECT[[Doxorubicin hydrochloride]] |
| | IUPAC_name = (8''S'',10''S'')-10-(4-amino-5-hydroxy-6-methyl-<br/>tetrahydro-2''H''-pyran-2-yloxy)<br/>-6,8,11-trihydroxy-8-(2-hydroxyacetyl)<br/>-1-methoxy-7,8,9,10-tetrahydrotetracene<br/>-5,12-dione
| |
| | image = Doxorubicin.jpg
| |
| | image2=Doxorubicin-3d-sticks.png
| |
| | CAS_number = 23214-92-8
| |
| | ATC_prefix = L01
| |
| | ATC_suffix =DB01
| |
| | PubChem = 31703
| |
| | DrugBank = APRD00185
| |
| | chemical_formula =
| |
| | C = 27 |H = 29 |N = 1 |O = 11
| |
| | molecular_weight = 543.52 [[Gram|g]]/[[Mole (unit)|mol]]
| |
| | bioavailability = 5% (Oral)
| |
| | protein_bound =
| |
| | metabolism = [[CYP3A4]]
| |
| | elimination_half-life = 12-18.5 hours<ref name="Laginha">Laginha, K.M. "[http://clincancerres.aacrjournals.org/cgi/reprint/11/19/6944 Determination of Doxorubicin Levels in Whole Tumor and Tumor Nuclei in Murine Breast Cancer Tumors]." ''Clinical Cancer Research.'' [[October 1]], [[2005]]. Vol. 11 (19). Retrieved on [[April 19]], [[2007]].</ref>
| |
| | excretion = Biliary and fecal
| |
| | pregnancy_AU = D
| |
| | pregnancy_US = D
| |
| | pregnancy_category=
| |
| | legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| |
| | legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
| |
| | legal_UK = POM
| |
| | legal_US = Rx-only
| |
| | legal_status =
| |
| | routes_of_administration = [[Intravenous therapy|Intravenous]]
| |
| }}
| |
| {{SI}}
| |
| {{CMG}}
| |
| __NOTOC__
| |
| | |
| | |
| ==Overview==
| |
| | |
| '''Doxorubicin''' (trade name '''Adriamycin''') or '''hydroxyldaunorubicin''' is a [[DNA]]-interacting [[pharmaceutical|drug]] widely used in [[chemotherapy]]. It is an [[anthracycline]] [[antibiotic]] and structurely closely related to [[daunomycin]], and also [[intercalation (chemistry)|intercalates]] DNA. It is commonly used in the treatment of a wide range of [[cancer]]s.
| |
| | |
| The drug is administered by [[injection]], and may be sold under the brand names '''Adriamycin PFS''', '''Adriamycin RDF''', or '''Rubex'''.<ref name="mayo_info">"[http://www.mayoclinic.com/health/drug-information/DR202209 Doxorubicin (Systemic)]." ''[[Mayo Clinic]].'' Last updated on: [[June 15]], [[1999]]. Retrieved on [[April 19]], [[2007]].</ref> '''Doxil''' is a [[liposome]]-encapsulated dosage form of doxorubicin made by Ben Venue Laboratories for [[Johnson & Johnson]]. The main benefits of this form are a reduction in cardiotoxicity.
| |
| | |
| ==History==
| |
| The history of doxorubicin can be traced back to the 1950s, when an [[Italy|Italian]] research company, [[Farmitalia Research Laboratories]], began an organized effort to find anticancer compounds from soil-based [[microbe]]s. A soil sample was isolated from the area surrounding the [[Castel del Monte]], a 13th century castle. A new strain of ''[[Streptomyces|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 [[Murinae|murine tumor]]s. Since a group of [[France|French]] researchers discovered the same compound at about the same time, the two teams named the compound [[daunorubicin]], combining the name ''[[List of Illyrian tribes|Daunii]]'', 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.<ref name="weiss">Weiss, Raymond B. "The Anthracyclines: Will We Ever Find a Better Doxorubicin?" Seminars in Oncology. Vol. 19, No. 6. December 1992. pp. 670–686. PMID 1462166.</ref> 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.<ref name="TanC">Tan, C.; Tasaka, H.; Kou-Ping, Y.; et al. Daunomycin, An Antitumor Antibiotic, In the Treatment of Neoplastic Disease. Clinical Evaluation with Special Reference to Childhood Leukemia. 1967, ''Cancer'', 20, 333 – 353. PMID 4290058.</ref>
| |
| | |
| 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.<ref name="ArcamoneF_biotechbioeng">Arcamone, F.; Cassinelli, G.; Fantini, G.; et al. Adriamycin, 14-hydroxydaunomycin, A New Antitumor Antibiotic from S. peucetius var. caesius. 1969, ''Biotechnol. Bioeng.'', 11, 1101 – 1110. PMID 5365804. </ref> 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.<ref name="DiMarcoA">Di Marco, A.; Gaetani, M.; Scarpinato, B. Adriamycin (NSC-123,127): A New Antibiotic with Antitumor Activity. 1969, ''Cancer Chemotherapy Reports'', 53, 33 – 37. PMID 5772652.</ref>
| |
| | |
| Doxorubicin and daunorubicin together can be thought of as [[prototype]] compounds for the anthracyclines. 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).<ref name="weiss"/>
| |
| | |
| ==Biosynthesis==
| |
| {{main|Biosynthesis of doxorubicin}}
| |
| Doxorubicin (DXR) is a 14-[[hydroxylated]] version of [[daunorubicin]], the immediate precursor of DXR in its [[Biosynthesis|biosynthetic]] pathway. [[Daunorubicin]] is more abundantly found as a [[natural product]] because it is produced by a number of different [[wild type]] [[Strain (biology)|strain]]s of ''[[streptomyces]]''. 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.<ref name="pmid9864344">{{cite journal |author=Lomovskaya N, Otten SL, Doi-Katayama Y, ''et al'' |title=Doxorubicin overproduction in Streptomyces peucetius: cloning and characterization of the dnrU ketoreductase and dnrV genes and the doxA cytochrome P-450 hydroxylase gene |journal=J. Bacteriol. |volume=181 |issue=1 |pages=305-18 |year=1999 |pmid=9864344 |doi=}}</ref> This strain was created by Arcamone et. al in 1969 by [[mutation| mutating]] a [[Strain (biology)|strain]] producing daunorubicin, but not DXR, at least in detectable quantities.<ref name="pmid5365804">{{cite journal |author=Arcamone F, Cassinelli G, Fantini G, ''et al'' |title=Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. caesius |journal=Biotechnol. Bioeng. |volume=11 |issue=6 |pages=1101-10 |year=1969 |pmid=5365804 |doi=10.1002/bit.260110607}}</ref> Subsequently, Hutchinson's group showed that under special environmental conditions, or by the introduction of [[Modifications (genetics)|genetic modifications]], other strains of ''streptomyces'' can produce doxorubicin.<ref name="pmid7828855">{{cite journal |author=Grimm A, Madduri K, Ali A, Hutchinson CR |title=Characterization of the Streptomyces peucetius ATCC 29050 genes encoding doxorubicin polyketide synthase |journal=Gene |volume=151 |issue=1-2 |pages=1-10 |year=1994 |pmid=7828855 |doi=}}</ref> His group has also [[cloned]] many of the [[genes]] required for DXR production, although not all of them have been fully characterized. In 1996, Strohl's group discovered, isolated and characterized dox A, the [[gene]] encoding the [[enzyme]] that converts daunorubicin into DXR.<ref name="pmid8655530">{{cite journal |author=Dickens ML, Strohl WR |title=Isolation and characterization of a gene from Streptomyces sp. strain C5 that confers the ability to convert daunomycin to doxorubicin on Streptomyces lividans TK24 |journal=J. Bacteriol. |volume=178 |issue=11 |pages=3389-95 |year=1996 |pmid=8655530 |doi=}}</ref> 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.<ref name="pmid9864343">{{cite journal |author=Walczak RJ, Dickens ML, Priestley ND, Strohl WR |title=Purification, properties, and characterization of recombinant Streptomyces sp. strain C5 DoxA, a cytochrome P-450 catalyzing multiple steps in doxorubicin biosynthesis |journal=J. Bacteriol. |volume=181 |issue=1 |pages=298-304 |year=1999 |pmid=9864343 |doi=}}</ref> 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. Hutchinson's group went on to develop methods to improve the yield of DXR, from the [[Industrial fermentation|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]].<ref name="pmid9864344">{{cite journal |author=Lomovskaya N, Otten SL, Doi-Katayama Y, ''et al'' |title=Doxorubicin overproduction in Streptomyces peucetius: cloning and characterization of the dnrU ketoreductase and dnrV genes and the doxA cytochrome P-450 hydroxylase gene |journal=J. Bacteriol. |volume=181 |issue=1 |pages=305-18 |year=1999 |pmid=9864344 |doi=}}</ref> Some triple mutants, that also [[gene expression|over-expressed]] Dox A, were able to double the yield of DXR. 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.<ref name="pmid10455495">{{cite journal |author=Hutchinson CR, Colombo AL |title=Genetic engineering of doxorubicin production in Streptomyces peucetius: a review |journal=J. Ind. Microbiol. Biotechnol. |volume=23 |issue=1 |pages=647-52 |year=1999 |pmid=10455495 |doi=}}</ref> More efficient production techniques have brought the price down to $1.1 million per kg for the non-[[liposomal]] formulation. Although DXR can be produced [[semisynthesis|semi-synthetically]] from daunorubicin, the process involves [[electrophilic]] [[bromination]] and multiple steps and the yield is poor.<ref name="pmid8022857">{{cite journal |author=Lown JW |title=Anthracycline and anthraquinone anticancer agents: current status and recent developments |journal=Pharmacol. Ther. |volume=60 |issue=2 |pages=185-214 |year=1993 |pmid=8022857 |doi=}}</ref> Since daunorubicin is produced by [[Fermentation (biochemistry)|fermentation]], it would be ideal if the [[bacteria]] could complete DXR synthesis more effectively.
| |
| | |
| ==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.<ref name="fornari">Fornari, F.A.; Randolph, J.K.; Yalowich, J.C.; Ritke, M.K.; Gewirtz, D.A. Interference by Doxorubicin with DNA Unwinding in MCF-7 Breast Tumor Cells. 1994, '''Molecular Pharmacology''', ''45'', 649 – 656. PMID 8183243.</ref> Doxorubicin is known to interact with DNA by [[Intercalation (disambiguation)|intercalation]] and inhibition of macromolecular [[biosynthesis]].<ref name="momparler">Momparler, R.L.; Karon, M.; Siegel, S.E.; Avila, F. Effect of Adriamycin on DNA, RNA and Protein Synthesis in Cell-Free Systems and Intact Cells. 1976, '''Cancer Research''', ''36'', 2891 – 2895. PMID 1277199. [http://cancerres.aacrjournals.org/cgi/reprint/36/8/2891 Free full text]</ref> This inhibits the progression of the enzyme [[topoisomerase II]], which unwinds DNA for [[Transcription (genetics)|transcription]]. 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 [[DNA replication|replication]].
| |
| | |
| 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.<ref name="frederick">Frederick, C.A.; Williams, L.D.; Ughetto, G.; van der Marel, G.A.; van Boom, J.H.; Rich, A.; Wang, A.H. Structural Comparison of Anticancer Drug-DNA Complexes: Adriamycin and Daunomycin. 1990, ''Biochemistry'', '''29''', 2538 – 2549. PMID 2334681. Crystal structure is available for download as a [http://www.rcsb.org/pdb/explore.do?structureId=1D12 PDB] file.</ref><ref name="pigram">Pigram, W.J.; Fuller, W.; Hamilton, L.D. Stereochemistry of Intercalation: Interaction of Daunomycin with DNA. 1972, '''Nature New Biology''', ''235'', 17 – 19. PMID 4502404.</ref>
| |
| | |
| ==Clinical use==
| |
| Doxorubicin is commonly used to treat some [[leukemia]]s, [[Hodgkin's lymphoma]], as well as cancers of the [[bladder cancer|bladder]], [[breast cancer|breast]], [[stomach cancer|stomach]], [[lung cancer|lung]], [[ovarian cancer|ovaries]], [[thyroid cancer|thyroid]], [[soft tissue sarcoma]], [[multiple myeloma]], and others.<ref name="mayo_info"/> Commonly used doxorubicin-containing [[chemotherapy regimen|regimens]] are CA (cyclophosphamide, Adriamycin), TAC (Taxotere, CA), [[ABVD]] (Adriamycin, [[Bleomycin]], [[Vinblastine]], [[Dacarbazine]]), [[CHOP]] ([[Cyclophosphamide]], Adriamycin, [[Vincristine]], [[Prednisone]]) and FAC (5-Fluorouracil, Adriamycin, Cyclophosphamide). 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]].<ref name="Doxil_info">"[http://www.orthobiotech.com/common/prescribing_information/DOXIL/PDF/DOXIL_PI_Booklet.pdf DOXIL Product Information]." ''[http://www.orthobiotech.com/ Ortho Biotech Products, L.P.]'' Retrieved on [[April 19]], [[2007]].</ref>
| |
| | |
| ===Experimental therapy===
| |
| [[Combination therapy]] experiments with [[sirolimus]] (rapamycin) and doxorubicin have shown promise in treating [[Akt]]-positive [[lymphoma]]s in mice.<ref>{{cite journal |author=Wendel H, De Stanchina E, Fridman J, Malina A, Ray S, Kogan S, Cordon-Cardo C, Pelletier J, Lowe S |title=Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy |journal=[[Nature (journal)|Nature]] |volume=428 |issue=6980 |pages=332–7 |year=2004 |pmid=15029198}}</ref>
| |
| | |
| Recent animal research coupling a [[Murinae|murine]] [[monoclonal antibody]] with doxorubicin has created an [[immunoconjugate]] that was able to eliminate [[HIV|HIV-1]] infection in mice. Current treatment with [[antiretroviral drug|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 cell]]s.<ref>{{cite journal | author = Johansson S, Goldenberg D, Griffiths G, Wahren B, Hinkula J | title = Elimination of HIV-1 infection by treatment with a doxorubicin-conjugated anti-envelope antibody. | journal = AIDS | volume = 20 | issue = 15 | pages = 1911-1915 | year = 2006 | id = PMID 16988511}}</ref>
| |
| | |
| ==Side effects==
| |
| Acute side-effects of doxorubicin can include nausea, vomiting, and heart [[arrhythmia]]s. It can also cause [[neutropenia]] (a decrease in [[white blood cell]]s), as well as complete [[alopecia]] (hair loss). 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. Doxorubicin cardiotoxicity is characterized by a dose-dependent decline in [[mitochondria]]l [[oxidative phosphorylation]]. 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.<ref name="Doxil_info"/>
| |
| | |
| Due to these side effects and its red color, doxorubicin has earned the nickname "red devil." <ref name="BlochCancerFaq">{{cite web | last=Bloch | first=Richard | coauthors=Bloch, Annette | title = 25 Most Asked Questions | work=Fighting Cancer | publisher=R. A. Bloch Cancer Foundation | url=http://www.blochcancer.org/fighting/chap13.html | accessdate = 2007-06-28 }}</ref>
| |
| | |
| ==See also==
| |
| * [[Anthracycline]]
| |
| * [[Chemotherapy regimen]]
| |
| * [[History of cancer chemotherapy]]
| |
| * [[ABVD]]
| |
| * [[CHOP]]
| |
| | |
| ==References==
| |
| <!-- ----------------------------------------------------------
| |
| See http://en.wikipedia.org/wiki/Wikipedia:Footnotes for a
| |
| discussion of different citation methods and how to generate
| |
| footnotes using the <ref>, </ref> and <reference /> tags
| |
| ----------------------------------------------------------- -->
| |
| {{Reflist|2}}
| |
| | |
| ==External links==
| |
| * {{MedlinePlusDrugInfo|medmaster|a682221}}
| |
| *[http://www.bccancer.bc.ca/HPI/DrugDatabase/DrugIndexPro/Doxorubicin.htm Overview] at [[BC Cancer Agency]]
| |
| *[http://www.orthobiotech.com/doxil.html Doxil Site]
| |
| *[http://www.virtualcancercentre.com/drugs.asp?drugid=1723 Adriamycin Solution / Doxorubicin hydrochloride] Virtual Cancer Centre
| |
| {{Chemotherapeutic Agents}}
| |
| | |
| <br>
| |
| [[Category:Chemotherapeutic agents]]
| |
| | |
| [[de:Doxorubicin]]
| |
| [[fr:Doxorubicine]]
| |
| [[hu:Doxorubicin]]
| |
| [[nl:Doxorubicine]]
| |
| [[ja:塩酸ドキソルビシン]]
| |
| [[pl:Doksorubicyna]]
| |
| [[zh:阿黴素]]
| |
| | |
| {{jb1}}
| |
| | |
| {{WikiDoc Help Menu}}
| |
| {{WikiDoc Sources}}
| |