Misplaced Pages

Doxorubicin: Difference between revisions

Article snapshot taken from[REDACTED] with creative commons attribution-sharealike license. Give it a read and then ask your questions in the chat. We can research this topic together.
Browse history interactively
Page 1
Page 2
← Previous editContent deleted Content addedVisualWikitext
Revision as of 11:45, 1 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,084 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'ChEMBL', 'StdInChI').← Previous edit Latest revision as of 16:47, 12 January 2025 edit undoArthurfragoso (talk | contribs)Extended confirmed users, Template editors4,591 edits dark mode fix 
(399 intermediate revisions by more than 100 users not shown)
Line 1: Line 1:
{{Short description|Chemotherapy medication}}
{{Drugbox
{{Use dmy dates|date=March 2023}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox drug
| Verifiedfields = changed | Verifiedfields = changed
| Watchedfields = changed | Watchedfields = changed
| verifiedrevid = 400825834 | verifiedrevid = 458446335
| drug_name =
| IUPAC_name = (7S,9S)-7-oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione
| INN =
| image = Doxorubicin.svg
| type = <!-- empty -->
| image = Doxorubicin.svg
| image_class = skin-invert-image
| width =
| alt =
| image2 = Doxorubicin 3D ball.png
| width2 =
| alt2 =
| caption =


<!--Clinical data--> <!-- Clinical data -->
| pronounce = {{IPAc-en|ˌ|d|ɒ|k|s|ə|ˈ|r|uː|b|ᵻ|s|ɪ|n}}
| tradename = Doxil
| tradename = Adriamycin, Caelyx,<ref name="Caelyx pegylated liposomal EPAR" /> Myocet,<ref name="Myocet liposomal EPAR" /> others
| Drugs.com = {{drugs.com|monograph|doxorubicin-hydrochloride}} | Drugs.com = {{drugs.com|monograph|doxorubicin-hydrochloride}}
| MedlinePlus = a682221 | MedlinePlus = a682221
| licence_CA = <!-- Health Canada may use generic or brand name (generic name preferred) -->
| licence_EU = yes
| DailyMedID = Doxorubicin
| licence_US = <!-- FDA may use generic or brand name (generic name preferred) -->
| pregnancy_AU = D | pregnancy_AU = D
| pregnancy_AU_comment =
| pregnancy_US = D
| pregnancy_category = | pregnancy_category =
| routes_of_administration = ], ]
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| class =
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
| ATCvet =
| ATC_prefix = L01
| ATC_suffix = DB01
| ATC_supplemental =
| biosimilars = Zolsketil pegylated liposomal,<ref name="Zolsketil pegylated liposomal EPAR" /> Celdoxome pegylated liposomal<ref name="Celdoxome pegylated liposomal EPAR" />

<!-- Legal status -->
| legal_AU = S4
| legal_AU_comment =
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->
| legal_BR_comment =
| legal_CA = Rx-only
| legal_CA_comment = <ref>{{cite web | title=Caelyx product information | website=] | date=25 April 2012 | url=https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=61804 | access-date=20 June 2022 | archive-date=21 June 2022 | archive-url=https://web.archive.org/web/20220621054714/https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=61804 | url-status=live }}</ref><ref>{{cite web | title=Myocet product information | website=] | date=25 April 2012 | url=https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=69014 | access-date=20 June 2022}}</ref><ref>{{cite web | title=Taro-doxorubicin liposomal product information | website=] | date=25 April 2012 | url=https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=98300 | access-date=20 June 2022 | archive-date=14 May 2021 | archive-url=https://web.archive.org/web/20210514034702/https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=98300 | url-status=live }}</ref>
| legal_DE = <!-- Anlage I, II, III or Unscheduled-->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = POM | legal_UK = POM
| legal_UK_comment =
| legal_US = Rx-only | legal_US = Rx-only
| legal_US_comment =
| legal_status =
| legal_EU = Rx-only
| routes_of_administration = ]
| legal_EU_comment = <ref name="Caelyx pegylated liposomal EPAR">{{cite web | title=Caelyx pegylated liposomal EPAR | website=] (EPAR) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/caelyx-pegylated-liposomal | access-date=20 June 2022 | archive-date=21 June 2022 | archive-url=https://web.archive.org/web/20220621052132/https://www.ema.europa.eu/en/medicines/human/EPAR/caelyx-pegylated-liposomal | url-status=live }}</ref><ref name="Myocet liposomal EPAR" /><ref name="Zolsketil pegylated liposomal EPAR" /><ref name="Celdoxome pegylated liposomal EPAR">{{cite web | title=Celdoxome pegylated liposomal EPAR | website=] (EMA) | date=20 June 2022 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/celdoxome-pegylated-liposomal | access-date=31 January 2023}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref>
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_UN_comment =
| legal_status = Rx-only


<!--Pharmacokinetic data--> <!-- Pharmacokinetic data -->
| bioavailability = 5% (Oral) | bioavailability = 5% (by mouth)
| protein_bound = | protein_bound = 75%<ref name = MSR/>
| metabolism = ] | metabolism = Liver
| metabolites =
| elimination_half-life = 12–18.5 hours when released from liposomes <ref name="Laginha">Laginha, K.M. "." ''Clinical Cancer Research.'' October 1, 2005. Vol. 11 (19). Retrieved on April 19, 2007.</ref>
| onset =
| excretion = Biliary and fecal
| elimination_half-life = Triphasic; 12 minutes, 3.3 hours, 30 hours. Mean: 1–3 hours<ref name=MSR>{{cite web|title=(doxorubicin) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=15 April 2014|url=http://reference.medscape.com/drug/doxorubicin-342120#showall|url-status=live|archive-url=https://web.archive.org/web/20140416181339/http://reference.medscape.com/drug/doxorubicin-342120#showall|archive-date=16 April 2014}}</ref><ref name = MD>{{cite web|title=Doxorubicin|work=Martindale: The Complete Drug Reference|publisher=Pharmaceutical Press|date=19 December 2013|access-date=15 April 2014| veditors = Brayfield A |url= http://www.medicinescomplete.com/mc/martindale/current/ms-21514-e.htm |archive-date=28 August 2021 |archive-url= https://web.archive.org/web/20210828065005/https://about.medicinescomplete.com/wp-content/themes/mc-marketing/assets/images/favicons-tiles/favicon.ico |url-status=live}}</ref>
| duration_of_action =
| excretion = Urine (5–12%), faeces (40–50%)<ref name = MSR/>


<!--Identifiers--> <!-- Identifiers -->
| index2_label = as HCl
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}} | CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 23214-92-8 | CAS_number = 23214-92-8
| CAS_number2 = 25316-40-9
| ATC_prefix = L01
| CAS_supplemental =
| ATC_suffix = DB01
| PubChem = 31703 | PubChem = 31703
| PubChem2 = 443939
| IUPHAR_ligand = 7069
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00997 | DrugBank = DB00997
| DrugBank2 = DBSALT000060
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 29400 | ChemSpiderID = 29400
| ChemSpiderID2 = 391993
| UNII_Ref = {{fdacite|correct|FDA}} | UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 80168379AG | UNII = 80168379AG
| UNII2 = 82F2G7BL4E
| KEGG_Ref = {{keggcite|changed|kegg}}
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D03899 | KEGG = D03899
| KEGG2 = D01275
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 28748 | ChEBI = 28748
| ChEBI2 = 31522
| ChEMBL_Ref = {{ebicite|changed|EBI}} | ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = <!-- blanked - oldvalue: 179 --> | ChEMBL = 53463
| ChEMBL2 = 359744
| C=27 | H=29 | N=1 | O=11
| NIAID_ChemDB =
| molecular_weight = 543.52 ]/]
| PDB_ligand =
| smiles = C1((C(O1)O2C(Cc3c2c(c4c(c3O)C(=O)c5cccc(c5C4=O)OC)O)(C(=O)CO)O)N)O
| synonyms =
| 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
<!-- Chemical and physical data -->
| IUPAC_name = (7''S'',9''S'')-7-oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7''H''-tetracene-5,12-dione
| C=27 | H=29 | N=1 | O=11
| SMILES = C1((C(O1)O2C(Cc3c2c(c4c(c3O)C(=O)c5cccc(c5C4=O)OC)O)(C(=O)CO)O)N)O
| StdInChI_Ref = {{stdinchicite|changed|chemspider}} | StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| 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 | 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
| StdInChI_comment =
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = AOJJSUZBOXZQNB-TZSSRYMLSA-N | StdInChIKey = AOJJSUZBOXZQNB-TZSSRYMLSA-N
| density =
| density_notes =
| melting_point =
| melting_high =
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| sol_units =
| specific_rotation =
}} }}
'''Doxorubicin''' (], {{pron-en|ˌdɒksəˈruːbəsɪn}}; trade name '''Adriamycin'''; also known as '''hydroxydaunorubicin''') is a ] used in cancer ]. It is an ] ], closely related to the ] ], and like all anthracyclines, it works by ] DNA.


<!-- Definition and medical uses -->
Doxorubicin is commonly used in the treatment of a wide range of ]s, including ], many types of ], and ]s.
'''Doxorubicin''', sold under the brand name '''Adriamycin''' among others, is a ] used to treat ].<ref name=AHFS2017/> This includes ], ], ], ], and ].<ref name=AHFS2017/> It is often used ].<ref name=AHFS2017/> Doxorubicin is given by ].<ref name=AHFS2017/>


<!-- Side effects and mechanism-->
Doxorubicin's most serious adverse effect is life-threatening heart damage.
Common side effects include ], ], ], rash, and ].<ref name=AHFS2017/> Other serious side effects may include ] such as ], ], tissue damage at the site of injection, ], and treatment-related ].<ref name=AHFS2017/> People often experience red discoloration of the urine for a few days.<ref name=AHFS2017/> Doxorubicin is in the ] and ] family of medications.<ref name=AHFS2017/> It works in part by interfering with the function of ].<ref name =Ta2013>{{cite journal | vauthors = Tacar O, Sriamornsak P, Dass CR | title = Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems | journal = The Journal of Pharmacy and Pharmacology | volume = 65 | issue = 2 | pages = 157–170 | date = February 2013 | pmid = 23278683 | doi = 10.1111/j.2042-7158.2012.01567.x | s2cid = 34737360 | doi-access = free }}</ref>


<!-- History society and culture -->
The drug is administered ], in the form of ]. It may be sold under the brand names '''Adriamycin PFS''', '''Adriamycin RDF''', or '''Rubex'''.<ref name="mayo_info">"." ''].'' 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.
Doxorubicin was approved for medical use in the United States in 1974.<ref name=AHFS2017>{{cite web|title=Doxorubicin Hydrochloride|url=https://www.drugs.com/monograph/doxorubicin-hydrochloride.html|publisher=The American Society of Health-System Pharmacists|access-date=12 January 2017|url-status=live|archive-url=https://web.archive.org/web/20161011065815/https://www.drugs.com/monograph/doxorubicin-hydrochloride.html|archive-date=11 October 2016}}</ref> It is on the ].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref><ref name=BNF69/> Versions that are ] and in ] are also available; however, they are more expensive.<ref name=BNF69>{{cite book|title=British national formulary : BNF 69|date=2015|publisher=British Medical Association|isbn=9780857111562|page=583|edition=69}}</ref> Doxorubicin was originally made from the bacterium '']''.<ref>{{cite book| vauthors = Ravina E |title=The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs|date=2011|publisher=John Wiley & Sons|isbn=9783527326693|page=291|url=https://books.google.com/books?id=iDNy0XxGqT8C&pg=PA291|language=en|url-status=live|archive-url=https://web.archive.org/web/20170918185523/https://books.google.com/books?id=iDNy0XxGqT8C&pg=PA291|archive-date=18 September 2017}}</ref>


== Medical uses ==
The molecule was originally isolated in the 1950s from bacteria found in soil samples taken from ], an ] castle.
In the EU doxorubicin pegylated liposomal (as Caelyx) is ] to treat breast cancer, ovarian cancer, and AIDS-related Kaposi's sarcoma. It is indicated to treat ] in combination with ].<ref name="Caelyx pegylated liposomal EPAR" /> Doxorubicin hydrochloride (as Myocet liposomal) is indicated to treat breast cancer in combination with ].<ref name="Myocet liposomal EPAR" />


Doxorubicin is commonly used to treat some ]s and ], as well as cancers of the ], ], ], ], ], ], ] as well as ] (desmoid tumor), ], and others.<ref name="MD" /><ref name="AMH" /><ref name="Alman_2020">{{cite journal |vauthors=Alman B, Attia S, Baumgarten C, Benson C, Blay JY, Bonvalot S, etal |date=March 2020 |title=The management of desmoid tumours: A joint global consensus-based guideline approach for adult and paediatric patients |journal=European Journal of Cancer |volume=127 |pages=96–107 |doi=10.1016/j.ejca.2019.11.013 |pmid=32004793 |s2cid=210998595 |doi-access=free |hdl-access=free |collaboration=Desmoid Tumor Working Group |hdl=2318/1793788}}</ref> Commonly used doxorubicin-containing ] are AC (Adriamycin, ]), TAC (], AC), ] (Adriamycin, ], ], ]), ], ] (cyclophosphamide, hydroxydaunorubicin, ], ]) and FAC (], adriamycin, cyclophosphamide).<ref name = MD/> Its activity is inhibited by certain antioxidant plant extracts, for example '']'' aqueous extract.<ref>{{Cite journal | vauthors = Bailon-Moscoso N, Coronel-Hidalgo J, Duarte-Casar R, Guamán-Ortiz LM, Figueroa JG, Romero-Benavides JC |date= November 2023 |title=Exploring the Antioxidant Potential of Tragia volubilis L.: Mitigating Chemotherapeutic Effects of Doxorubicin on Tumor Cells |journal=Antioxidants |language=en |volume=12 |issue=11 |pages=2003 |doi=10.3390/antiox12112003 |issn=2076-3921|doi-access=free |pmid= 38001856 |pmc= 10669231 }}</ref>
== History ==
{{see also|History of cancer chemotherapy}}
The history of doxorubicin can be traced back to the 1950s, when an ] research company, Farmitalia Research Laboratories, began an organized effort to find anticancer compounds from soil-based ]s. A soil sample was isolated from the area surrounding the ], a 13th century castle. A new strain of '']'', which produced a red pigment, was isolated, and an antibiotic was produced from this bacterium that was found to have good activity against ]. Since a group of ] researchers discovered the same compound at about the same time, the two teams named the compound ], combining the name '']'', a pre-Roman tribe that occupied the area of Italy where the compound was isolated, with the French word for ], ''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>


Doxil (see below) is used primarily for the treatment of ovarian cancer where the disease has progressed or recurred after ], or for the treatment of ]-related ].<ref name="Doxil_info">"{{cite web | url = http://www.orthobiotech.com/common/prescribing_information/DOXIL/PDF/DOXIL_PI_Booklet.pdf | title = DOXIL Product Information | archive-url = https://web.archive.org/web/20070921075517/http://www.orthobiotech.com/common/prescribing_information/DOXIL/PDF/DOXIL_PI_Booklet.pdf | archive-date=September 21, 2007 | access-date = 19 April 2007 }}</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 ], 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 ] 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>


== Side effects ==
Doxorubicin and daunorubicin together can be thought of as ] 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 ] (NCI).<ref name="weiss"/>
===Cardiotoxicity===
The most dangerous side effect of doxorubicin is ], leading to ]. The rate of cardiomyopathy is dependent on its cumulative dose, with an incidence about 4% when the dose of doxorubicin is 500–550&nbsp;mg/m<sup>2</sup>, 18% when the dose is 551–600&nbsp;mg/m<sup>2</sup> and 36% when the dose exceeds 600&nbsp;mg/m<sup>2</sup>.<ref name="Chaterjee">{{cite journal | vauthors = Chatterjee K, Zhang J, Honbo N, Karliner JS | title = Doxorubicin cardiomyopathy | journal = Cardiology | volume = 115 | issue = 2 | pages = 155–162 | date = January 2010 | pmid = 20016174 | pmc = 2848530 | doi = 10.1159/000265166 }}</ref> There are several ways in which doxorubicin is believed to cause cardiomyopathy, including ] due to iron accumulation, downregulation of genes for contractile proteins, and ]-mediated ].<ref name=Chaterjee /><ref>{{cite journal | vauthors = Ichikawa Y, Ghanefar M, Bayeva M, Wu R, Khechaduri A, Naga Prasad SV, Mutharasan RK, Naik TJ, Ardehali H | title = Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation | journal = The Journal of Clinical Investigation | volume = 124 | issue = 2 | pages = 617–630 | date = February 2014 | pmid = 24382354 | doi = 10.1172/JCI72931 | pmc = 3904631 }}</ref>


Doxorubicin-induced cardiomyopathy typically results in dilated cardiomyopathy, with all four cardiac chambers being enlarged.<ref name=Chat2010/> This results in both systolic and diastolic dysfunction.<ref name=Chat2010/> Eventually, heart failure can result, which carries a 50% mortality rate.<ref name=Chat2010>{{cite journal | vauthors = Chatterjee K, Zhang J, Honbo N, Karliner JS | title = Doxorubicin cardiomyopathy | journal = Cardiology | volume = 115 | issue = 2 | pages = 155–162 | date = 2010 | pmid = 20016174 | pmc = 2848530 | doi = 10.1159/000265166 }}</ref> There is no effective treatment against established cardiomyopathy caused by the drug as of 2010.<ref name=Chat2010/> The drug ], which is an iron ] may be used to decrease the risk of doxorubicin's cardiotoxicity in certain cases.<ref>{{cite web |title=Dexrazoxane Hydrochloride Monograph for Professionals - Drugs.com |url=https://www.drugs.com/monograph/dexrazoxane-hydrochloride.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |access-date=1 August 2018 |archive-date=1 August 2018 |archive-url=https://web.archive.org/web/20180801124706/https://www.drugs.com/monograph/dexrazoxane-hydrochloride.html |url-status=live }}</ref>
== Clinical use ==
Doxorubicin is commonly used to treat some ]s and ], as well as cancers of the ], ], ], ], ], ], ], ], and others.<ref name="mayo_info"/> Commonly used doxorubicin-containing ] are AC (Adriamycin, ]), TAC (], CA), ] (Adriamycin, ], ], ]), ], ] (], Adriamycin, ], ]) and FAC (], Adriamycin, ]).


Doxil (see below) is used primarily for the treatment of ovarian cancer where the disease has progressed or recurred after ], or for the treatment of ]-related ].<ref name="Doxil_info">"." '''' 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 === ===Other===
Another common and potentially fatal complication of doxorubicin is ], an acute life-threatening inflammation of the bowel.<ref>{{cite journal | vauthors = Kaczmarek A, Brinkman BM, Heyndrickx L, Vandenabeele P, Krysko DV | title = Severity of doxorubicin-induced small intestinal mucositis is regulated by the TLR-2 and TLR-9 pathways | journal = The Journal of Pathology | volume = 226 | issue = 4 | pages = 598–608 | date = March 2012 | pmid = 21960132 | doi = 10.1002/path.3009 | s2cid = 206325412 }}{{Dead link|date=November 2021 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> Additionally, some people may develop ] (PPE), characterized by skin eruptions on the palms of the hand or soles of the feet, swelling, pain, and ].<ref name="Doxil_info"/> Due to these side effects and its red color, doxorubicin has earned the nickname "red devil"<ref>{{Cite web | url=https://voice.ons.org/news-and-views/outpatient-oncology-drug-series-doxorubicin-is-the-infamous-red-devil | title=Outpatient Oncology Drug Series: Doxorubicin is the Infamous Red Devil | access-date=21 April 2018 | archive-date=21 April 2018 | archive-url=https://web.archive.org/web/20180421163336/https://voice.ons.org/news-and-views/outpatient-oncology-drug-series-doxorubicin-is-the-infamous-red-devil | url-status=live }}</ref><ref name="BlochCancerFaq">{{cite web | vauthors = Bloch R, Bloch A | title = 25 Most Asked Questions | work=Fighting Cancer | publisher=R. A. Bloch Cancer Foundation | url=http://www.blochcancer.org/fighting/chap13.html | access-date = 28 June 2007 |archive-url = https://web.archive.org/web/20070626082335/http://www.blochcancer.org/fighting/chap13.html |archive-date = 26 June 2007|url-status=dead}}</ref> or "red death."<ref>{{cite book | vauthors = Groopman JE |author-link=Jerome Groopman |title=How Doctors Think |publisher=Houghton Mifflin |location=Boston |year=2007 |isbn=978-0-618-61003-7 |page=|title-link=How Doctors Think }}</ref>
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, "J&J is Short of Cancer Drug Doxil", Wall Street Journal, July 21, 2011</ref>.


Chemotherapy can cause reactivation of ], and doxorubicin-containing regimens are no exception.<ref>{{cite journal | vauthors = Yeo W, Lam KC, Zee B, Chan PS, Mo FK, Ho WM, Wong WL, Leung TW, Chan AT, Ma B, Mok TS, Johnson PJ | title = Hepatitis B reactivation in patients with hepatocellular carcinoma undergoing systemic chemotherapy | journal = Annals of Oncology | volume = 15 | issue = 11 | pages = 1661–1666 | date = November 2004 | pmid = 15520068 | doi = 10.1093/annonc/mdh430 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Dillon R, Hirschfield GM, Allison ME, Rege KP | title = Fatal reactivation of hepatitis B after chemotherapy for lymphoma | journal = BMJ | volume = 337 | pages = a423 | date = July 2008 | pmid = 18595895 | doi = 10.1136/bmj.39490.680498.BE | s2cid = 11661945 }}</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> 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, "UPDATE: Ben Venue to Exit Drug Contract Manufacturing Business," Wall Street Journal, August 19, 2011</ref>.


Doxorubicin and several chemotherapeutic drugs (including cyclophosphamide) can cause a loss of ].<ref>{{cite web |url=http://www.nejm.org/image-challenge?ci=09012011&query=TOC |title=Image Challenge &#124; NEJM |access-date=1 September 2011 |url-status=live |archive-url=https://web.archive.org/web/20130316203047/http://www.nejm.org/image-challenge?ci=09012011&query=TOC |archive-date=16 March 2013 }}</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 , 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 </ref>.


===Liposomal formulations===
=== Experimental therapy ===
<!-- Liposomal doxorubicin, Doxil, Caelyx, Myocet redirect here! -->
] experiments with ] (rapamycin) and doxorubicin have shown promise in treating ]-positive ]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=] |volume=428 |issue=6980 |pages=332–7 |year=2004 |pmid=15029198 |doi=10.1038/nature02369}}</ref>
{{anchor|Liposomal form}}


There is a ] (polyethylene glycol coated) ]-encapsulated form of doxorubicin, developed to treat ]. The ] coating results in preferential concentration of doxorubicin in the skin. However, this also results in a side effect called palmar plantar erythrodysesthesia (PPE), more commonly known as hand-foot syndrome.
Recent animal research coupling a ] ] with doxorubicin has created an ] that was able to eliminate ] infection in mice. Current treatment with ] (ART) still leaves pockets of HIV within the host. The immunoconjugate could potentially provide a complementary treatment to ART to eradicate antigen-expressing ]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>


Following administration of this form of doxorubicin, 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/m<sup>2</sup> dosing every four weeks, half of people developed hand-foot syndrome. The rate of this side effect limits the dose of this formulation that can be given as compared with plain doxorubicin in the same treatment regimen, thereby limiting potential substitution. Substitution would be desirable because liposome-encapsulated doxorubicin is less cardiotoxic than unencapsulated doxorubicin. This liposome-encapsulated form 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=1 April 2009 |access-date=27 November 2009 |url-status=live |archive-url=https://web.archive.org/web/20091129030936/http://www.macmillan.org.uk/Cancerinformation/Cancertreatment/Treatmenttypes/Chemotherapy/Individualdrugs/Liposomaldoxorubicin.aspx |archive-date=29 November 2009 }}</ref><ref>{{cite web |url=http://www.chemocare.com/bio/doxorubicin_liposomal.asp |title=Doxorubicin liposomal |publisher=] |work=Chemocare |access-date=27 November 2009 |url-status=live |archive-url=https://web.archive.org/web/20100102095755/http://chemocare.com/bio/doxorubicin_liposomal.asp |archive-date=2 January 2010 }}</ref>
===Liposomal formulations===<!--Liposomal doxorubicin, Doxil, Caelyx, Myocet redirect here!-->
'''Doxil''' is a ] (polyethylene glycol coated) ]-encapsulated form of doxorubicin formerly made by ] in the United States for ], a subsidiary of ]. It was developed to treat ], an ]-related cancer that causes lesions to grow under the skin, in the lining of the mouth, nose and throat, or in other organs. The ] coating results in preferential concentration of Doxil in the skin. However, this also results in a side effect called ] (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/m<sup>2</sup> 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=] |work=Chemocare |accessdate=2009-11-27}}</ref> Outside the United States, Doxil is known as Caelyx and is marketed by ].


''']'''<ref name=Macmillan/> is a non-pegylated liposomal doxorubicin made by ] for ] 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 ], 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 ] (Herceptin) and ] (Taxol) for treatment of ]-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 ] (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 ] function, while still achieving superior tumor response. This finding is the basis for the on-going phase III trial for FDA approval. A non-pegylated liposomal doxorubicin, called Myocet, is approved in the European Union and in Canada for the treatment of metastatic breast cancer in combination with ],<ref name="Myocet liposomal EPAR">{{cite web | title=Myocet liposomal EPAR | website=European Medicines Agency | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/myocet-liposomal-previously-myocet | access-date=20 June 2022 | archive-date=25 February 2022 | archive-url=https://web.archive.org/web/20220225004945/https://www.ema.europa.eu/en/medicines/human/EPAR/myocet-liposomal-previously-myocet | url-status=live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> but it has not been approved by the FDA for use in the United States. Unlike Doxil, the Myocet liposome does not have a polyethylene glycol coating, and therefore does not result in the same rate of PPE. The minimization of this side effect may allow for one-for-one (1:1) 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 ]. There is an FDA black box warning that trastuzumab 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 ] (CHF). Published phase II study results have shown that Myocet, trastuzumab, and ] can safely be used concurrently without the cardiac risk, as measured by reduction in ] function, while still achieving superior tumor response. This finding is the basis for the ongoing phase III trial for FDA approval.<ref name=Macmillan/>


== Adverse effects == == Biosynthesis ==
{{main|Biosynthesis of doxorubicin}}
Acute ] of doxorubicin can include nausea, vomiting, and heart ]s. It can also cause ] (a decrease in ]s), as well as complete ] (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 ], and death, dramatically increase. Doxorubicin cardiotoxicity is characterized by a dose-dependent decline in ]l ]. 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 ], characterized by skin eruptions on the palms of the hand or soles of the feet, swelling, pain and ].<ref name="Doxil_info"/>
Doxorubicin (DXR) is a 14-] version of ], the immediate precursor of DXR in its ] pathway.


] is more abundantly found as a ] because it is produced by a number of different ] ] of '']''. In contrast, only one known non-] ], '']'' ] ''cesius'' ATCC 27952, was initially found to be capable of producing the more widely used doxorubicin.<ref name="pmid9864344">{{cite journal | vauthors = Lomovskaya N, Otten SL, Doi-Katayama Y, Fonstein L, Liu XC, Takatsu T, Inventi-Solari A, Filippini S, Torti F, Colombo AL, Hutchinson CR | 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 = Journal of Bacteriology | volume = 181 | issue = 1 | pages = 305–318 | date = January 1999 | pmid = 9864344 | pmc = 103563 | doi = 10.1128/JB.181.1.305-318.1999 }}</ref> This strain was created by Arcamone et al. in 1969 by ] a strain producing daunorubicin, but not DXR, at least in detectable quantities.<ref name="pmid5365804">{{cite journal | vauthors = Arcamone F, Cassinelli G, Fantini G, Grein A, Orezzi P, Pol C, Spalla C | title = Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. caesius | journal = Biotechnology and Bioengineering | volume = 11 | issue = 6 | pages = 1101–1110 | date = November 1969 | pmid = 5365804 | doi = 10.1002/bit.260110607 | s2cid = 21897153 }}</ref> Subsequently, Hutchinson's group showed that under special environmental conditions, or by the introduction of ], other strains of ''Streptomyces'' can produce doxorubicin.<ref name="pmid7828855">{{cite journal | vauthors = 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 | date = December 1994 | pmid = 7828855 | doi = 10.1016/0378-1119(94)90625-4 | doi-access = free }}</ref> His group also ] many of the ] 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 ] encoding the ] that converts daunorubicin into DXR.<ref name="pmid8655530">{{cite journal | vauthors = 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 = Journal of Bacteriology | volume = 178 | issue = 11 | pages = 3389–3395 | date = June 1996 | pmid = 8655530 | pmc = 178102 | doi = 10.1128/jb.178.11.3389-3395.1996 }}</ref>
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>


By 1999, they produced recombinant dox A, a ], and found that it ] multiple steps in DXR ], including steps leading to daunorubicin.<ref name="pmid9864343">{{cite journal | vauthors = 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 = Journal of Bacteriology | volume = 181 | issue = 1 | pages = 298–304 | date = January 1999 | pmid = 9864343 | pmc = 103562 | doi = 10.1128/JB.181.1.298-304.1999 }}</ref> This was significant because it became clear that all daunorubicin-producing strains have the necessary ] 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 ] process used in its commercial production, not only by introducing dox A encoding ], but also by introducing mutations to deactivate ] that shunt DXR precursors to less useful products, for example baumycin-like ].<ref name="pmid9864344"/> Some triple mutants, that also ] 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 | vauthors = Hutchinson CR, Colombo AL | title = Genetic engineering of doxorubicin production in Streptomyces peucetius: a review | journal = Journal of Industrial Microbiology & Biotechnology | volume = 23 | issue = 1 | pages = 647–652 | date = July 1999 | pmid = 10455495 | doi = 10.1038/sj.jim.2900673 | s2cid = 27337697 }}</ref>
Chemotherapy can cause reactivation of ], 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=] |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=] |volume=337 |issue= |pages=a423 |year=2008 |pmid=18595895 |doi=10.1136/bmj.39490.680498.BE}}</ref>


More efficient production techniques have brought the price down to $1.1 million per kg for the non] formulation. Although DXR can be produced ] from daunorubicin, the process involves ] ] and multiple steps, and the yield is poor.<ref name="pmid8022857">{{cite journal | vauthors = Lown JW | title = Anthracycline and anthraquinone anticancer agents: current status and recent developments | journal = Pharmacology & Therapeutics | volume = 60 | issue = 2 | pages = 185–214 | date = November 1993 | pmid = 8022857 | doi = 10.1016/0163-7258(93)90006-Y }}</ref> Since daunorubicin is produced by ], it would be ideal if the ] could complete DXR synthesis more effectively.
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-] version of ], the immediate precursor of DXR in its ] pathway. ] is more abundantly found as a ] because it is produced by a number of different ] ] of '']''. In contrast, only one known non-] ], ''Streptomyces peucetius'' ] ''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 ] 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 ], 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 ] many of the ] 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 ] encoding the ] 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 ], and found that it ] multiple steps in DXR ], 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 ] 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 ] process used in its commercial production, not only by introducing dox A encoding ], but also by introducing mutations to deactivate ] that shunt DXR precursors to less useful products, for example baumycin-like ].<ref name="pmid9864344"/> Some triple mutants, that also ] 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] formulation. Although DXR can be produced ] from daunorubicin, the process involves ] ] 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 ], it would be ideal if the ] could complete DXR synthesis more effectively.


== Mechanism of action == == Mechanism of action ==
] ]
Doxorubicin interacts with DNA by ] and inhibition of macromolecular ].<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=] |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 ], which relaxes supercoils in DNA for ]. 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 ].


Doxorubicin interacts with DNA by ] and inhibition of macromolecular ].<ref name =Ta2013/><ref name="fornari">{{cite journal | vauthors = 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 | volume = 45 | issue = 4 | pages = 649–656 | date = April 1994 | pmid = 8183243 }}</ref><ref name="momparler">{{cite journal | vauthors = 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 Research | volume = 36 | issue = 8 | pages = 2891–2895 | date = August 1976 | pmid = 1277199 | url = http://cancerres.aacrjournals.org/cgi/reprint/36/8/2891 | url-status = live | archive-url = https://web.archive.org/web/20090205063327/http://cancerres.aacrjournals.org/cgi/reprint/36/8/2891 | archive-date = 5 February 2009 }}</ref> This inhibits the progression of ], an enzyme which relaxes supercoils in DNA for ].<ref>{{cite journal | vauthors = Pommier Y, Leo E, Zhang H, Marchand C | title = DNA topoisomerases and their poisoning by anticancer and antibacterial drugs | journal = Chemistry & Biology | volume = 17 | issue = 5 | pages = 421–433 | date = May 2010 | pmid = 20534341 | pmc = 7316379 | doi = 10.1016/j.chembiol.2010.04.012 | doi-access = free }}</ref> Doxorubicin stabilizes the topoisomerase II complex after it has broken the DNA chain for replication, preventing the DNA double helix from being released and thereby stopping the process of ].<ref name =Ta2013/> It may also increase quinone type free radical production, hence contributing to its cytotoxicity.<ref name="AMH">{{cite book | veditors = Rossi S | isbn = 978-0-9805790-9-3 | title = Australian Medicines Handbook | place = Adelaide | publisher = The Australian Medicines Handbook Unit Trust | year = 2013 | edition = 2013 }}</ref>
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 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>


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 | vauthors = Frederick CA, Williams LD, Ughetto G, van der Marel GA, van Boom JH, Rich A, Wang AH | title = Structural comparison of anticancer drug-DNA complexes: adriamycin and daunomycin | journal = Biochemistry | volume = 29 | issue = 10 | pages = 2538–2549 | date = March 1990 | pmid = 2334681 | doi = 10.1021/bi00462a016 }} Crystal structure is available for download as a {{webarchive|url=https://web.archive.org/web/20080114013050/http://www.rcsb.org/pdb/explore.do?structureId=1D12 |date=14 January 2008 }} file.</ref><ref name="pigram">{{cite journal | vauthors = Pigram WJ, Fuller W, Hamilton LD | title = Stereochemistry of intercalation: interaction of daunomycin with DNA | journal = Nature | volume = 235 | issue = 53 | pages = 17–19 | date = January 1972 | pmid = 4502404 | doi = 10.1038/newbio235017a0 }}</ref>
== Antimalarial activity ==


By ], doxorubicin can also induce ] eviction from transcriptionally active ].<ref name="Pang">{{cite journal | vauthors = Pang B, Qiao X, Janssen L, Velds A, Groothuis T, Kerkhoven R, Nieuwland M, Ovaa H, Rottenberg S, van Tellingen O, Janssen J, Huijgens P, Zwart W, Neefjes J | title = Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin | journal = Nature Communications | volume = 4 | issue = 5 | pages = 1908 | year = 2013 | pmid = 23715267 | pmc = 3674280 | doi = 10.1038/ncomms2921 | bibcode = 2013NatCo...4.1908P }}</ref><ref name="pang">{{cite journal | vauthors = Pang B, de Jong J, Qiao X, Wessels LF, Neefjes J | title = Chemical profiling of the genome with anti-cancer drugs defines target specificities | journal = Nature Chemical Biology | volume = 11 | issue = 7 | pages = 472–480 | date = July 2015 | pmid = 25961671 | doi = 10.1038/nchembio.1811 }}</ref> As a result, the ], ] and ] are deregulated in doxorubicin-exposed cells.<ref name="Pang"/>
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 ] II, an enzyme unique to the malarial parasite '']''.<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 ] (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 == == History ==
].]]
* ]
{{see also|Anthracycline#History|Daunorubicin#History|History of cancer chemotherapy}}
** ]
In the 1950s, an Italian research company, ] Research Laboratories, began an organized effort to find anticancer compounds from soil-based microbes. A soil sample was isolated from the area surrounding the ], a 13th-century castle. A new strain of '']'', which produced a red pigment, was isolated, and an antibiotic from this bacterium was effective against tumors in mice. Since a group of French researchers discovered the same compound at about the same time, the two teams named the compound ], combining the name '']'', a pre-Roman tribe that occupied the area of Italy where the compound was isolated, with the French word for ], ''rubis'', describing the color.<ref name="weiss">{{cite journal | vauthors = Weiss RB | title = The anthracyclines: will we ever find a better doxorubicin? | journal = Seminars in Oncology | volume = 19 | issue = 6 | pages = 670–686 | date = December 1992 | pmid = 1462166 }}</ref><ref>{{cite journal | vauthors = Baruffa G | title = Clinical trials in Plasmodium falciparum malaria with a long-acting sulphonamide | journal = Transactions of the Royal Society of Tropical Medicine and Hygiene | volume = 60 | issue = 2 | pages = 222–224 | year = 1966 | pmid = 5332105 | doi = 10.1016/0035-9203(66)90030-7 }}</ref><ref>Per prior citation, the first publication: {{cite journal | vauthors = Camerino B, Palamidessi G | date = 1960 | title = Derivati della parazina II. Sulfonamdopir | language = Italian | journal = Gazz Chim Ital | volume = 90 | pages = 1802–1815 }}</ref> Clinical trials began in the 1960s, and the drug was successful in treating acute leukemia and lymphoma. However, by 1967, it was recognized that daunorubicin could lead to fatal cardiac toxicity.<ref name="TanC">{{cite journal | vauthors = 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 = 333–353 | date = March 1967 | pmid = 4290058 | doi = 10.1002/1097-0142(1967)20:3<333::AID-CNCR2820200302>3.0.CO;2-K | s2cid = 19272219 | doi-access = free }}</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 ], 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 mouse tumors, and especially solid tumors. It also showed a higher ], yet the ] remained.<ref name="DiMarcoA">{{cite journal | vauthors = Di Marco A, Gaetani M, Scarpinato B | title = Adriamycin (NSC-123,127): a new antibiotic with antitumor activity | journal = Cancer Chemotherapy Reports | volume = 53 | issue = 1 | pages = 33–37 | date = February 1969 | pmid = 5772652 }}</ref>

Doxorubicin and daunorubicin together can be thought of as prototype compounds for the ]s. Subsequent research has led to many other anthracycline antibiotics, or analogs, and there are now over 2,000 known analogs of doxorubicin. By 1991, 553 of them had been evaluated in the screening program at the ] (NCI).<ref name="weiss"/> In 2016 GPX-150 was granted ] designation by US FDA.<ref> {{webarchive|url=https://web.archive.org/web/20160124010110/http://www.cancernetwork.com/sarcoma/investigational-sarcoma-drug-gpx-150-gets-orphan-drug-designation |date=24 January 2016 }}</ref>

==Society and culture==

=== Legal status ===
On 24 March 2022, the ] (CHMP) of the ] (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Zolsketil pegylated liposomal, intended for the treatment of metastatic breast cancer, advanced ovarian cancer, progressive multiple myeloma and AIDS-related Kaposi's sarcoma.<ref name="Zolsketil pegylated liposomal: Pending EC decision" /> The applicant for this medicinal product is Accord Healthcare S.L.U.<ref name="Zolsketil pegylated liposomal: Pending EC decision" /> Zolsketil pegylated liposomal is a hybrid medicine of Adriamycin.<ref name="Zolsketil pegylated liposomal: Pending EC decision" /> It contains the same active substance as Adriamycin, but is available in a pegylated liposomal formulation.<ref name="Zolsketil pegylated liposomal: Pending EC decision">{{cite web | title=Zolsketil pegylated liposomal: Pending EC decision | website=] (EMA) | date=24 March 2022 | url=https://www.ema.europa.eu/en/medicines/human/summaries-opinion/zolsketil-pegylated-liposomal | access-date=29 March 2022 | archive-date=29 March 2022 | archive-url=https://web.archive.org/web/20220329163755/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/zolsketil-pegylated-liposomal | url-status=live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> Zolsketil pegylated liposomal was approved for medical use in the European Union in May 2022.<ref name="Zolsketil pegylated liposomal EPAR">{{cite web | title=Zolsketil pegylated liposomal EPAR | website=] (EMA) | date=24 January 2022 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/zolsketil-pegylated-liposomal | access-date=20 June 2022 | archive-date=21 June 2022 | archive-url=https://web.archive.org/web/20220621052452/https://www.ema.europa.eu/en/medicines/human/EPAR/zolsketil-pegylated-liposomal | url-status=live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref><ref>{{cite web | title=Zolsketil Product information | website=Union Register of medicinal products | url=https://ec.europa.eu/health/documents/community-register/html/h1629.htm | access-date=3 March 2023}}</ref>

On 21 July 2022, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Celdoxome pegylated liposomal, intended for the treatment of metastatic breast cancer, advanced ovarian cancer, progressive multiple myeloma and AIDS-related Kaposi's sarcoma.<ref name="Celdoxome pegylated liposomal: Pending EC decision" /> The applicant for this medicinal product is YES Pharmaceutical Development Services GmbH.<ref name="Celdoxome pegylated liposomal: Pending EC decision">{{cite web | title=Celdoxome pegylated liposomal: Pending EC decision | website=] (EMA) | date=22 July 2022 | url=https://www.ema.europa.eu/en/medicines/human/summaries-opinion/celdoxome-pegylated-liposomal | access-date=30 July 2022 | archive-date=28 July 2022 | archive-url=https://web.archive.org/web/20220728183716/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/celdoxome-pegylated-liposomal | url-status=live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> Celdoxome pegylated liposomal is a hybrid medicine of Adriamycin which has been authorized in the EU since 24 October 1979.<ref name="Celdoxome pegylated liposomal: Pending EC decision" /> Celdoxome pegylated liposomal contains the same active substance as Adriamycin, but is available in a pegylated liposomal formulation.<ref name="Celdoxome pegylated liposomal: Pending EC decision" /> Celdoxome pegylated liposomal was approved for medical use in the European Union in September 2022.<ref name="Celdoxome pegylated liposomal EPAR" />

===Names===
It is also known as hydroxydaunorubicin and hydroxydaunomycin.<ref>{{Cite web|title=Doxorubicin: MedlinePlus Drug Information|url=https://medlineplus.gov/druginfo/meds/a682221.html|access-date=12 July 2020|website=medlineplus.gov|language=en|archive-date=13 July 2020|archive-url=https://web.archive.org/web/20200713131707/https://medlineplus.gov/druginfo/meds/a682221.html|url-status=live}}</ref>

It is sold under a number of different brand names, including Adriamycin PFS, Adriamycin RDF, or Rubex.<ref name=MD/>

===Formulations===
Doxorubicin is photosensitive, and containers are often covered by an aluminum bag and/or brown wax paper to prevent light from affecting it.<ref name = MD/> Doxorubicin is also available in ]-encapsulated forms as Doxil (] form), Myocet (nonpegylated form), and Caelyx,<ref name="Caelyx pegylated liposomal EPAR" /> which are also given by intravenous injection.<ref name = MD/>

The FDA approved the first generic version of Doxil, made by Sun, in February 2013.<ref>{{cite press release |url=https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm337872.htm |title=FDA approval of generic version of cancer drug Doxil is expected to help resolve shortage |publisher=U.S. ] (FDA) |date=4 February 2013 |access-date=22 February 2014 |url-status=dead |archive-url=https://web.archive.org/web/20140228161954/https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm337872.htm |archive-date=28 February 2014 }}</ref>

==Research==

] experiments with ] (rapamycin) and doxorubicin have shown promise in treating ]-positive ]s in mice.<ref>{{cite journal | vauthors = Wendel HG, De Stanchina E, Fridman JS, Malina A, Ray S, Kogan S, Cordon-Cardo C, Pelletier J, Lowe SW | title = Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy | journal = Nature | volume = 428 | issue = 6980 | pages = 332–337 | date = March 2004 | pmid = 15029198 | doi = 10.1038/nature02369 | s2cid = 4426215 | bibcode = 2004Natur.428..332W }}</ref>

Further, the release of photo-activated adriamycin with the aid of nanoporous optical antenna resulted in significant anti-cancer effect in MCF-7 breast cancer cells.<ref name=":1">{{cite journal | vauthors = Saha T, Mondal J, Khiste S, Lusic H, Hu ZW, Jayabalan R, Hodgetts KJ, Jang H, Sengupta S, Eunice Lee S, Park Y, Lee LP, Goldman A | title = Nanotherapeutic approaches to overcome distinct drug resistance barriers in models of breast cancer | journal = Nanophotonics | volume = 10 | issue = 12 | pages = 3063–3073 | date = September 2021 | pmid = 34589378 | pmc = 8478290 | doi = 10.1515/nanoph-2021-0142 | bibcode = 2021Nanop..10..142S | doi-access = free }}</ref> In 2006, animal research coupling a ] ] with doxorubicin created an ] that was able to eliminate ] infection in mice.<ref>{{cite journal | vauthors = Johansson S, Goldenberg DM, Griffiths GL, 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 | date = October 2006 | pmid = 16988511 | doi = 10.1097/01.aids.0000247111.58961.60 | s2cid = 42286690 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Mitsuyasu R | title = Curing HIV: lessons from cancer therapy | language = en-US | journal = Current Opinion in HIV and AIDS | volume = 8 | issue = 3 | pages = 224–229 | date = May 2013 | pmid = 23454863 | pmc = 3789644 | doi = 10.1097/COH.0b013e32835ef0a1 }}</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 ] II, an enzyme unique to the malarial parasite '']''.<ref name="friedman">{{cite journal | vauthors = Friedman R, Caflisch A | title = Discovery of plasmepsin inhibitors by fragment-based docking and consensus scoring | journal = ChemMedChem | volume = 4 | issue = 8 | pages = 1317–1326 | date = August 2009 | pmid = 19472268 | doi = 10.1002/cmdc.200900078 | url = http://www3.interscience.wiley.com/journal/122407624/abstract?CRETRY=1&SRETRY=0 | url-status = dead | access-date = 28 May 2010 | s2cid = 14642593 | archive-url = https://archive.today/20130105091659/http://www3.interscience.wiley.com/journal/122407624/abstract?CRETRY=1&SRETRY=0 | archive-date = 5 January 2013 }}</ref> The pharmaceutical company ] (GSK) later identified doxorubicin in a set of compounds that inhibit parasite growth.<ref name="Gamo">{{cite journal | vauthors = Gamo FJ, Sanz LM, Vidal J, de Cozar C, Alvarez E, Lavandera JL, Vanderwall DE, Green DV, Kumar V, Hasan S, Brown JR, Peishoff CE, Cardon LR, Garcia-Bustos JF | title = Thousands of chemical starting points for antimalarial lead identification | journal = Nature | volume = 465 | issue = 7296 | pages = 305–310 | date = May 2010 | pmid = 20485427 | doi = 10.1038/nature09107 | s2cid = 1143258 | bibcode = 2010Natur.465..305G }}</ref>

=== Fluorescence ===
Doxorubicin is also known to be fluorescent. This has often been used to characterize doxorubicin concentrations, and has opened the possibility of using the molecule as a ] agent. However, there are significant limitations, as doxorubicin's fluorescence spectrum is known to depend on a variety of factors, including the pH of the environment, solvent ] and others. Doxorubicin fluorescence is quenched by binding to DNA, and shielded by micelle encapsulation. It is also known to self-quench at high concentrations. In contrast, histone binding amplifies fluorescence.<ref>{{cite journal | vauthors = Karukstis KK, Thompson EH, Whiles JA, Rosenfeld RJ | title = Deciphering the fluorescence signature of daunomycin and doxorubicin | journal = Biophysical Chemistry | volume = 73 | issue = 3 | pages = 249–263 | date = July 1998 | pmid = 9700924 | doi = 10.1016/s0301-4622(98)00150-1 }}</ref><ref>{{cite journal | vauthors = Mohan P, Rapoport N | title = Doxorubicin as a molecular nanotheranostic agent: effect of doxorubicin encapsulation in micelles or nanoemulsions on the ultrasound-mediated intracellular delivery and nuclear trafficking | journal = Molecular Pharmaceutics | volume = 7 | issue = 6 | pages = 1959–1973 | date = December 2010 | pmid = 20957997 | pmc = 2997862 | doi = 10.1021/mp100269f }}</ref>


== References == == References ==
{{Reflist}}
<!-- ----------------------------------------------------------
See http://en.wikipedia.org/Wikipedia:Footnotes for a
discussion of different citation methods and how to generate
footnotes using the<ref>, </ref> and<reference /> tags
----------------------------------------------------------- -->
{{Reflist|colwidth=30em}}


== External links == == External links ==
* {{Commonscatinline}}
* {{MedlinePlusDrugInfo|medmaster|a682221}}
* {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/doxorubicin | publisher = U.S. National Library of Medicine| work = Drug Information Portal | title = Doxorubicin }}
* at ]
* {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/doxorubicin%20hydrochloride | publisher = U.S. National Library of Medicine| work = Drug Information Portal | title = Doxorubicin hydrochloride }}
*

* Virtual Cancer Centre
*
{{-}}
{{Chemotherapeutic Agents}} {{Chemotherapeutic Agents}}
{{good article}} {{Portal bar|Medicine}}
{{Authority control}}
{{Good article}}


] ]
] ]
] ]
]
]
] ]
]

]
]
]
]
]
]
]
]
]
]
]
]
]
]
]
]
]
]
]
]
]
Doxorubicin: Difference between revisions Add topic