Doxorubicin: Difference between revisions

{{Drugbox

| verifiedrevid = 400825834

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

<!--Clinical data-->

| tradename = Doxil

| 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_status =

| routes_of_administration = [[Intravenous therapy|Intravenous]]

<!--Pharmacokinetic data-->

| bioavailability = 5% (Oral)

| protein_bound =

| metabolism = [[CYP3A4]]

| elimination_half-life = 12–18.5 hours when released from liposomes <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

<!--Identifiers-->

| CASNo_Ref = {{cascite|correct|CAS}}

| ATC_prefix = L01

| ATC_suffix = DB01

| KEGG_Ref = {{keggcite|changed|kegg}}

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEMBL = <!-- blanked - oldvalue: 179 -->

| C=27 | H=29 | N=1 | O=11

| molecular_weight = 543.52 [[Gram|g]]/[[Mole (unit)|mol]]

| smiles = 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)CO)O)N)O

| InChI = 1/C27H29NO11/c1-10-22(31)13(28)6-17(38-10)39-15-8-27(36,16(30)9-29)7-12-19(15) 26(35)21-20(24(12)33)23(32)11-4-3-5-14(37-2)18(11)25(21)34/h3-5,10,13,15, 17,22,29,31,33,35-36H,6-9,28H2,1-2H3/t10-,13-,15-,17-,22+,27-/m0/s1

| InChIKey = AOJJSUZBOXZQNB-TZSSRYMLBG

| StdInChI = 1S/C27H29NO11/c1-10-22(31)13(28)6-17(38-10)39-15-8-27(36,16(30)9-29)7-12-19(15)26(35)21-20(24(12)33)23(32)11-4-3-5-14(37-2)18(11)25(21)34/h3-5,10,13,15,17,22,29,31,33,35-36H,6-9,28H2,1-2H3/t10-,13-,15-,17-,22+,27-/m0/s1

'''Doxorubicin''' ([[International Nonproprietary Name|INN]], {{pron-en|ˌdɒksəˈruːbəsɪn}}; trade name '''Adriamycin'''; also known as '''hydroxydaunorubicin''') is a [[pharmaceutical|drug]] used in cancer [[chemotherapy]]. It is an [[anthracycline]] [[antibiotic]], closely related to the [[natural product]] [[daunorubicin|daunomycin]], and like all anthracyclines, it works by [[intercalation (chemistry)|intercalating]] DNA.

Doxorubicin is commonly used in the treatment of a wide range of [[cancer]]s, including [[hematological malignancy|hematological malignancies]], many types of [[carcinoma]], and [[soft tissue sarcoma]]s.

Doxorubicin's most serious adverse effect is life-threatening heart damage.

The drug is administered [[intravenous therapy|intravenously]], in the form of [[hydrochloride salt]]. It 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. {{Wayback|url=http://www.mayoclinic.com/health/drug-information/DR202209|date =20070403223644|bot=DASHBot}}</ref> Doxorubicin is photosensitive, and containers are often covered by an aluminum bag and/or brown wax paper to prevent light from affecting it.

The molecule was originally isolated in the 1950s from bacteria found in soil samples taken from [[Castel del Monte, Apulia|Castel del Monte]], an [[Italy|Italian]] castle.

== History ==

{{see also|History of cancer chemotherapy}}

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, Apulia|Castel del Monte]], a 13th century castle. A new strain of ''[[Streptomyces|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 [[Murinae|murine tumors]]. 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 ''[[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.<ref name="weiss">{{cite journal |author=Weiss RB |title=The anthracyclines: will we ever find a better doxorubicin? |journal=Seminars in Oncology |volume=19 |issue=6 |pages=670–86 |year=1992 |month=December |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">{{cite journal |doi=10.1002/1097-0142(1967)20:3<333::AID-CNCR2820200302>3.0.CO;2-K |author=Tan C, Tasaka H, Yu KP, Murphy ML, Karnofsky DA |title=Daunomycin, an antitumor antibiotic, in the treatment of neoplastic disease. Clinical evaluation with special reference to childhood leukemia |journal=Cancer |volume=20 |issue=3 |pages=333–53 |year=1967 |month=March |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="pmid5365804"/> Doxorubicin showed better activity than daunorubicin against murine tumors, and especially solid tumors. It also showed a higher therapeutic index, yet the [[cardiotoxicity]] remained.<ref name="DiMarcoA">{{cite journal |author=Di Marco A, Gaetani M, Scarpinato B |title=Adriamycin (NSC-123,127): a new antibiotic with antitumor activity |journal=Cancer Chemother Rep |volume=53 |issue=1 |pages=33–7 |year=1969 |month=February |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 it is now estimated that there are over 2,000 known analogs of doxorubicin. By 1991, 553 of them had been evaluated in the screening program at the [[National Cancer Institute]] (NCI).<ref name="weiss"/>

== Clinical use ==

Doxorubicin is commonly used to treat some [[leukemia]]s and [[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 AC (Adriamycin, [[cyclophosphamide]]), TAC ([[Taxotere]], CA), [[ABVD]] (Adriamycin, [[bleomycin]], [[vinblastine]], [[dacarbazine]]), [[BEACOPP]], [[CHOP]] ([[cyclophosphamide]], Adriamycin, [[vincristine]], [[prednisone]]) and FAC ([[5-fluorouracil]], Adriamycin, [[cyclophosphamide]]).

Doxil (see below) is used primarily for the treatment of ovarian cancer where the disease has progressed or recurred after [[cisplatin|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. {{Wayback|url=http://www.orthobiotech.com/common/prescribing_information/DOXIL/PDF/DOXIL_PI_Booklet.pdf|date =20070921075517|bot=DASHBot}}</ref>

=== Doxil Shortage ===

Doxil is currently unavailable for clinical use (October 2011). ''Johnson & Johnson (JNJ)'', through it's subsidiary ''Janssen Products, LP'', had been receiving its Doxil supply from contract manufacturer ''Ben Venue Laboratories'' (located in Bedford, Ohio). Ben Venue is a unit of ''Boehringer Ingelheim GmbH'' of Germany. Ben Venue ceased manufacturing Doxil during Summer 2011 <ref>Peter Loftus, [http://online.wsj.com/article/SB10001424053111903554904576460290484704816.html] "J&J is Short of Cancer Drug Doxil", Wall Street Journal, July 21, 2011</ref>.

As of October 31, 2011, Janssen's website stated: "Janssen Products, LP strongly emphasizes that this DOXIL® supply shortage has been caused by capacity constraints at the specialty manufacturer we hired to make this medicine. These capacity constraints are due in part to unplanned downtime created by equipment failures. We are working closely with this supplier to restore uninterrupted access to DOXIL® as quickly as possible."<ref>[http://www.doxil.com/doxil-supply-shortage] Janssen website www.doxil.com on October 31, 2011</ref> In August 2011, Boehringer's Ben Venue Laboratories unit, which manufactures injectable and inhaled drugs for major companies including Pfizer Inc. (PFE) and Johnson & Johnson, announced that it will exit the contract-manufacturing business in a transition to focus on its generics business <ref>Peter Loftus, [http://online.wsj.com/article/BT-CO-20110819-712649.html] "UPDATE: Ben Venue to Exit Drug Contract Manufacturing Business," Wall Street Journal, August 19, 2011</ref>.

The patent for Doxil expired in October 2009, but Doxil is protected against generic competition until May 2014 because the FDA has granted it "orphan drug exclusivity"; that designation allows an extended period of protection as a way of rewarding companies who research and produce drugs used for rare conditions<ref>Online article by Kristi Monson, PharmD, for eMedTV [http://ovarian-cancer.emedtv.com/doxil/generic-doxil.html], last reviewed March 16, 2010</ref>. Drugs that qualify for orphan drug status are those that affect fewer than 200,000 people in the U.S., or that affect more than 200,000 persons but are not expected to recover the costs of developing and marketing a treatment drug <ref>FDA website [http://www.fda.gov/forindustry/developingproductsforrarediseasesconditions/default.htm]</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 |doi=10.1038/nature02369}}</ref>

Recent animal research coupling a [[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 complementary 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 | pmid = 16988511 | doi = 10.1097/01.aids.0000247111.58961.60}}</ref>

===Liposomal formulations===<!--Liposomal doxorubicin, Doxil, Caelyx, Myocet redirect here!-->

'''Doxil''' is a [[pegylated]] (polyethylene glycol coated) [[liposome]]-encapsulated form of doxorubicin formerly made by [[Ben Venue Laboratories]] in the United States for [[Janssen Products, LP]], a subsidiary of [[Johnson & Johnson]]. It was developed to treat [[Kaposi's sarcoma]], an [[AIDS]]-related cancer that causes lesions to grow under the skin, in the lining of the mouth, nose and throat, or in other organs. The [[polyethylene glycol]] coating results in preferential concentration of Doxil in the skin. However, this also results in a side effect called [[palmar plantar erythrodysesthesia]] (PPE), more commonly known as hand-foot syndrome. Following administration of Doxil, small amounts of the drug can leak from capillaries in the palms of the hands and soles of the feet. The result of this leakage is redness, tenderness, and peeling of the skin that can be uncomfortable and even painful. In clinical testing at 50&nbsp;mg/m² dosing every 4 weeks, 50.6% of patients treated with Doxil developed hand-foot syndrome. The prevalence of this side effect limits the Doxil dose that can be given as compared with doxorubicin in the same treatment regimen, thereby limiting potential substitution. Substitution would be desirable because liposome-encapsulated doxorubicin is less cardiotoxic than unencapsulated doxorubicin. Doxil is also approved by the FDA for treatment of ovarian cancer and multiple myeloma.<ref name=Macmillan>{{cite web |url=http://www.macmillan.org.uk/Cancerinformation/Cancertreatment/Treatmenttypes/Chemotherapy/Individualdrugs/Liposomaldoxorubicin.aspx |title=Liposomal doxorubicin (Caelyx, Myocet) |publisher=Macmillan Cancer Support |date=April 1, 2009 |accessdate=2009-11-27}}</ref><ref>{{cite web |url=http://www.chemocare.com/bio/doxorubicin_liposomal.asp |title=Doxorubicin liposomal |publisher=[[Cleveland Clinic]] |work=Chemocare |accessdate=2009-11-27}}</ref> Outside the United States, Doxil is known as Caelyx and is marketed by [[Janssen Pharmaceutica|Janssen]].

'''[[Myocet]]'''<ref name=Macmillan/> is a non-pegylated liposomal doxorubicin made by [[Enzon Pharmaceuticals]] for [[Cephalon]] in Europe and for Sopherion Therapeutics in the United States and Canada. Myocet is approved in Europe and Canada for treatment of metastatic breast cancer in combination with [[cyclophosphamide]], but is not yet approved by the FDA for use in the United States. It is currently being studied by Sopherion Therapeutics in a pivotal phase III global registrational trial in concurrent combination with [[trastuzumab]] (Herceptin) and [[paclitaxel]] (Taxol) for treatment of [[HER2]]-positive metastatic breast cancer. Unlike Doxil, the Myocet liposome does not have a polyethylene glycol coating, and therefore does not result in the same prevalence of hand-foot syndrome. The minimization of this side effect may allow for one for one substitution with doxorubicin in the same treatment regimen, thereby improving safety with no loss of efficacy. Like Doxil, the liposomal encapsulation of the doxorubicin limits the cardiotoxicity. In theory, by limiting the cardiotoxicity of doxorubicin through liposomal encapsulation, it can be used safely in concurrent combination with other cardiotoxic chemotherapy drugs, such as trastuzumab. There is an FDA black box warning that Herceptin cannot be used in concurrent combination with doxorubicin, only in sequential combination. Though concurrent combination of trastuzumab and doxorubicin in clinical studies found superior tumor response, the combination resulted in unacceptable cardiotoxicity, including risk of cardiac failure manifesting as [[congestive heart failure]] (CHF). Published phase II study results have shown that Myocet, trastuzumab, and paclitaxel can safely be used concurrently without the cardiac risk, as measured by reduction in [[LVEF]] function, while still achieving superior tumor response. This finding is the basis for the on-going phase III trial for FDA approval.

== Adverse effects ==

Acute [[adverse drug reaction|adverse 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). A more mild side effect is discoloration of the urine, which can turn bright red for up to 48 hours after dosing. When the cumulative dose of doxorubicin reaches 550&nbsp;mg/m², the risks of developing cardiac side effects, including CHF, 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|PPE]], characterized by skin eruptions on the palms of the hand or soles of the feet, 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 |archiveurl = http://web.archive.org/web/20070626082335/http://www.blochcancer.org/fighting/chap13.html |archivedate = June 26, 2007|deadurl=yes}}</ref> or "red death."<ref>{{cite book |author=Groopman, Jerome E. |authorlink=Jerome Groopman |title=How Doctors Think |publisher=Houghton Mifflin |location=Boston |year=2007 |isbn=0-618-61003-0 |page=49}}</ref>

Chemotherapy can cause reactivation of [[hepatitis B]], and doxorubicin-containing regimens are no exception.<ref>{{cite journal |author=Yeo W, Lam KC, Zee B, ''et al.'' |title=Hepatitis B reactivation in patients with hepatocellular carcinoma undergoing systemic chemotherapy |journal=[[Annals of Oncology|Ann Oncol]] |volume=15 |issue=11 |pages=1661–6 |year=2004 |month=November |pmid=15520068 |doi=10.1093/annonc/mdh430}}</ref><ref>{{cite journal |author=Dillon R, Hirschfield GM, Allison ME, Rege KP |title=Fatal reactivation of hepatitis B after chemotherapy for lymphoma |journal=[[BMJ]] |volume=337 |issue= |pages=a423 |year=2008 |pmid=18595895 |doi=10.1136/bmj.39490.680498.BE}}</ref>

Doxorubin and several chemotherapeutic drugs (including cyclophosphamide) cause dyspigmentation. Other groups of drugs that cause this problem include antimalarials, amiodarone, heavy metals (but not iron), tetracyclines, and antipsychotics. <ref>http://www.nejm.org/image-challenge?ci=09012011&query=TOC</ref>

== 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)|strains]] 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= |pmc=103563}}</ref> This strain was created by Arcamone et al. in 1969 by [[mutation|mutating]] a 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=10.1016/0378-1119(94)90625-4}}</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= |pmc=178102}}</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= |pmc=103562}}</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"/> 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&nbsp;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=10.1038/sj.jim.2900673}}</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=10.1016/0163-7258(93)90006-Y}}</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 ==

[[Image:Doxorubicin–DNA complex 1D12.png|thumb|Cartoon diagram of two doxorubicin molecules intercalating DNA, from {{PDB|1D12}}.<ref name=frederick/>]]

Doxorubicin interacts with DNA by [[Intercalation (chemistry)|intercalation]] and inhibition of macromolecular [[biosynthesis]].<ref name="fornari">{{cite journal |author=Fornari FA, Randolph JK, Yalowich JC, Ritke MK, Gewirtz DA |title=Interference by doxorubicin with DNA unwinding in MCF-7 breast tumor cells |journal=[[Molecular Pharmacology|Mol Pharmacol]] |volume=45 |issue=4 |pages=649–56 |year=1994 |month=April |pmid=8183243}}</ref><ref name="momparler">{{cite journal |author=Momparler RL, Karon M, Siegel SE, Avila F |title=Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells |journal=Cancer Res |volume=36 |issue=8 |pages=2891–5 |year=1976 |month=August |pmid=1277199 |url=http://cancerres.aacrjournals.org/cgi/reprint/36/8/2891}}</ref> This inhibits the progression of the enzyme [[topoisomerase II]], which relaxes supercoils in 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">{{cite journal |doi=10.1021/bi00462a016 |author=Frederick CA, Williams LD, Ughetto G, ''et al.'' |title=Structural comparison of anticancer drug-DNA complexes: adriamycin and daunomycin |journal=Biochemistry |volume=29 |issue=10 |pages=2538–49 |year=1990 |month=March |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">{{cite journal |author=Pigram WJ, Fuller W, Hamilton LD |title=Stereochemistry of intercalation: interaction of daunomycin with DNA |journal=Nature New Biol |volume=235 |issue=53 |pages=17–9 |year=1972 |month=January |pmid=4502404}}</ref>

== Antimalarial activity ==

There is some evidence for antimalarial activity for doxorubicin and similar compounds. In 2009, a compound similar in structure to doxorubicin was found to inhibit [[plasmepsin]] II, an enzyme unique to the malarial parasite ''[[Plasmodium falciparum]]''.<ref name="friedman">{{cite journal |author=Friedman R, Caflisch A |title= Discovery of Plasmepsin Inhibitors by Fragment-Based Docking and Consensus Scoring |journal=ChemMedChem |volume=4 |pages=1317–26 |year=2009 |url=http://www3.interscience.wiley.com/journal/122407624/abstract?CRETRY=1&SRETRY=0 |pmid=19472268 |issue=8 |doi=10.1002/cmdc.200900078}}</ref> The pharmaceutical company [[GlaxoSmithKline]] (GSK) later identified doxorubicin in a set of compounds that inhibit parasite growth <ref name="Gamo">{{cite journal |author= Gamo F-J et al.|title= Thousands of chemical starting points for antimalarial lead identification |journal= Nature |volume=465 |pages=305–310 |year=2010 |url=http://www.nature.com/nature/journal/v465/n7296/full/nature09107.html |pmid= 20485427 |issue= 7296 |doi= 10.1038/nature09107}}</ref>

== See also ==

* [[Chemotherapy regimen]]

** [[ABVD]]

** [[BEACOPP]]

** [[CHOP]]

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{{Reflist|colwidth=30em}}

* {{MedlinePlusDrugInfo|medmaster|a682221}}

* [http://www.bccancer.bc.ca/HPI/DrugDatabase/DrugIndexPro/Doxorubicin.htm Overview] at [[BC Cancer Agency]]

* [http://www.orthobiotech.com/orthobiotech/doxil.html Doxil Site]

* [http://www.virtualcancercentre.com/drugs.asp?drugid=1723 Adriamycin Solution / Doxorubicin hydrochloride] Virtual Cancer Centre

* [http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Doxorubicin U.S. National Library of Medicine: Drug Information Portal - Doxorubicin]

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[[Category:Polyphenol glycosides]]

[[Category:Topoisomerase inhibitors]]

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[[hu:Doxorubicin]]

[[nl:Doxorubicine]]

[[ja:ドキソルビシン]]

[[pl:Doksorubicyna]]

[[pt:Doxorrubicina]]

[[ru:Доксорубицин]]

[[fi:Doksorubisiini]]

[[tr:Doksorubisin]]

[[uk:Доксорубіцин]]

[[zh:阿黴素]]