Doxorubicin

{{Short description|Chemotherapy medication}} {{Use dmy dates|date=March 2023}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 458446335 | drug_name = | INN = | type =  | image = Doxorubicin.svg | image_class = skin-invert-image | width = | alt = | image2 = Doxorubicin ball-and-stick model from xtal 2018.png | image_class2 = bg-transparent | width2 = | alt2 = | caption =

| pronounce = {{IPAc-en|ˌ|d|ɒ|k|s|ə|ˈ|r|uː|b|ᵻ|s|ɪ|n}} | tradename = Adriamycin, Caelyx,<ref name="Caelyx pegylated liposomal EPAR" /> Myocet,<ref name="Myocet liposomal EPAR" /> others | Drugs.com = {{drugs.com|monograph|doxorubicin-hydrochloride}} | MedlinePlus = a682221 | licence_CA =  | licence_EU = yes | DailyMedID = Doxorubicin | licence_US =  | pregnancy_AU = D | pregnancy_AU_comment = | pregnancy_category = | routes_of_administration = intravenous, intravesical | class = | 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_AU = S4 | legal_AU_comment = | legal_BR =  | legal_BR_comment = | legal_CA = Rx-only | legal_CA_comment = <ref>{{cite web | title=Caelyx product information | website=Health Canada | 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=Health Canada | 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=Health Canada | 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 =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK = POM | legal_UK_comment = | legal_US = Rx-only | legal_US_comment = | legal_EU = Rx-only | legal_EU_comment = <ref name="Caelyx pegylated liposomal EPAR">{{cite web | title=Caelyx pegylated liposomal EPAR | website=European Medicines Agency (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=European Medicines Agency (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 =  | legal_UN_comment = | legal_status = Rx-only

| bioavailability = 5% (by mouth) | protein_bound = 75%<ref name = MSR/> | metabolism = Liver | metabolites = | onset = | 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/>

| index2_label = as HCl | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 23214-92-8 | CAS_number2 = 25316-40-9 | CAS_supplemental = | PubChem = 31703 | PubChem2 = 443939 | IUPHAR_ligand = 7069 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00997 | DrugBank2 = DBSALT000060 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 29400 | ChemSpiderID2 = 391993 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 80168379AG | UNII2 = 82F2G7BL4E | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D03899 | KEGG2 = D01275 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 28748 | ChEBI2 = 31522 | ChEMBL_Ref = {{ebicite|changed|EBI}} | ChEMBL = 53463 | ChEMBL2 = 359744 | NIAID_ChemDB = | PDB_ligand = | synonyms =

| IUPAC_name = (7''S'',9''S'')-7-[(2''R'',4''S'',5''S'',6''S'')-4-Amino-5-hydroxy-6-methyloxan-2-yl]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 = 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 | 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_comment = | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = AOJJSUZBOXZQNB-TZSSRYMLSA-N | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}

'''Doxorubicin''', sold under the brand name '''Adriamycin''' among others, is a chemotherapy medication used to treat cancer.<ref name=AHFS2017/> This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia.<ref name=AHFS2017/> It is often used together with other chemotherapy agents.<ref name=AHFS2017/> Doxorubicin is given by injection into a vein.<ref name=AHFS2017/>

Common side effects include hair loss, bone marrow suppression, vomiting, rash, and inflammation of the mouth.<ref name=AHFS2017/> Other serious side effects may include allergic reactions such as anaphylaxis, heart damage, tissue damage at the site of injection, radiation recall, and treatment-related leukemia.<ref name=AHFS2017/> People often experience red discoloration of the urine for a few days.<ref name=AHFS2017/> Doxorubicin is in the anthracycline and antitumor antibiotic family of medications.<ref name=AHFS2017/> It works in part by interfering with the function of DNA.<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>

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 World Health Organization's List of Essential Medicines.<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 pegylated and in liposomes 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 ''Streptomyces peucetius''.<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 == In the EU doxorubicin pegylated liposomal (as Caelyx) is indicated to treat breast cancer, ovarian cancer, and AIDS-related Kaposi's sarcoma. It is indicated to treat multiple myeloma in combination with bortezomib.<ref name="Caelyx pegylated liposomal EPAR" /> Doxorubicin hydrochloride (as Myocet liposomal) is indicated to treat breast cancer in combination with cyclophosphamide.<ref name="Myocet liposomal EPAR" />

Doxorubicin is commonly used to treat some leukemias and lymphomas, as well as cancers of the bladder, breast, stomach, lung, ovaries, thyroid, soft tissue sarcoma as well as aggressive fibromatosis (desmoid tumor), multiple myeloma, 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 regimens are AC (Adriamycin, cyclophosphamide), TAC (taxotere, AC), ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine), BEACOPP, CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone) and FAC (5-fluorouracil, adriamycin, cyclophosphamide).<ref name = MD/> Its activity is inhibited by certain antioxidant plant extracts, for example ''Tragia volubilis'' 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>

Doxil (see below) is used primarily for the treatment of ovarian cancer where the disease has progressed or recurred after platinum-based chemotherapy, or for the treatment of AIDS-related Kaposi's sarcoma.<ref name="Doxil_info">"{{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>

== Side effects == ===Cardiotoxicity=== The most dangerous side effect of doxorubicin is dilated cardiomyopathy, leading to congestive heart failure. The rate of cardiomyopathy is dependent on its cumulative dose, with an incidence about 4% when the dose of doxorubicin is 500–550 mg/m2, 18% when the dose is 551–600 mg/m2 and 36% when the dose exceeds 600 mg/m2.<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 oxidative stress due to iron accumulation, downregulation of genes for contractile proteins, and p53-mediated apoptosis.<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 dexrazoxane, which is an iron chelator, 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> ===Other=== Another common and potentially fatal complication of doxorubicin is typhlitis, 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 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>{{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> 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=[https://archive.org/details/howdoctorsthink00groo/page/49 49]|title-link=How Doctors Think }}</ref>

Chemotherapy can cause reactivation of hepatitis B, 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>

Doxorubicin and several chemotherapeutic drugs (including cyclophosphamide) can cause a loss of skin pigmentation.<ref>{{cite web |url=http://www.nejm.org/image-challenge?ci=09012011&query=TOC |title=Image Challenge | 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>

Doxorubicin has been linked to myopathy of the bladder's detrusor muscle, causing dysfunction of its contractile-relaxation mechanism and higher risk of lower urinary tract dysfunction (LUTD) than peers. It is recommended that childhood cancer survivors treated with doxorubicin be monitored for subsequent LUTD.<ref name="Hecht_2021">{{cite journal | vauthors = Hecht SL, Quach A, Gao D, Brazell A, Beltran G, Holbrook S, Gore L, Iguchi N, Malykhina A, Wilcox D, Cost NG | title = A prospective survey study of lower urinary tract dysfunction in childhood cancer survivors after vincristine and/or doxorubicin chemotherapy | journal = Pediatric Blood & Cancer | volume = 68 | issue = 10 | article-number = e29226 | date = October 2021 | pmid = 34245214 | pmc = 8384667 | doi = 10.1002/pbc.29226 }}</ref>

===Liposomal formulations===  {{anchor|Liposomal form}}

There is a pegylated (polyethylene glycol coated) liposome-encapsulated form of doxorubicin, developed to treat Kaposi's sarcoma. The polyethylene glycol 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.

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 mg/m2 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=Cleveland Clinic |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>

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 cyclophosphamide,<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 trastuzumab. There is an FDA boxed 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 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 ongoing phase III trial for FDA approval.<ref name=Macmillan/>

== Biosynthesis == {{main|Biosynthesis of doxorubicin}} Doxorubicin (DXR) is a 14-hydroxylated version of daunorubicin, the immediate precursor of DXR in its biosynthetic pathway.

Daunorubicin is more abundantly found as a natural product because it is produced by a number of different wild type 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 | 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 mutating 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 genetic modifications, 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 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 | 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>

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 | 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 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 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 over-expressed dox A, were able to double the yield of DXR. This is of more than academic interest, because at that time DXR cost about $1.37 million per kg and current production in 1999 was 225 kg per annum.<ref name="pmid10455495">{{cite journal | 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>

More efficient production techniques have brought the price down to $1.1 million per kg for the nonliposomal formulation. Although DXR can be produced semi-synthetically from daunorubicin, the process involves electrophilic bromination 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 fermentation, it would be ideal if the bacteria could complete DXR synthesis more effectively.

== Mechanism of action == thumb|Diagram of two doxorubicin molecules intercalating DNA, from {{PDB|1D12}}.<ref name=frederick/>

Doxorubicin interacts with DNA by intercalation and inhibition of macromolecular biosynthesis.<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 | doi = 10.1016/S0026-895X(25)10149-1 | 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 topoisomerase II, an enzyme which relaxes supercoils in DNA for transcription.<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 replication.<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 | 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 [http://www.rcsb.org/pdb/explore.do?structureId=1D12 PDB] {{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>

By intercalation, doxorubicin can also induce histone eviction from transcriptionally active chromatin.<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 | article-number = 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 DNA damage response, epigenome and transcriptome are deregulated in doxorubicin-exposed cells.<ref name="Pang"/>

== History == [[File:Andria - Castel del Monte - 202209012324.jpg|thumb|right|Bacteria producing doxorubicin were originally discovered in soil near Castel del Monte, Apulia.]] {{see also|Anthracycline#History|Daunorubicin#History|History of cancer chemotherapy}} In the 1950s, an Italian research company, Farmitalia Research Laboratories, began an organized effort to find anticancer compounds from soil-based microbes. A soil sample was isolated from the area surrounding the Castel del Monte, a 13th-century castle. A new strain of ''Streptomyces peucetius'', 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 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 {{Gloss|ruby}}, {{Lang|fr|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 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 mouse tumors, and especially solid tumors. It also showed a higher therapeutic index, yet the cardiotoxicity 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 anthracyclines. 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 National Cancer Institute (NCI).<ref name="weiss"/> In 2016 GPX-150 was granted orphan drug designation by US FDA.<ref>[http://www.cancernetwork.com/sarcoma/investigational-sarcoma-drug-gpx-150-gets-orphan-drug-designation Investigational Sarcoma Drug GPX-150 Gets Orphan Drug Designation. 2016] {{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 Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (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=European Medicines Agency (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=European Medicines Agency (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=European Medicines Agency (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 liposome-encapsulated forms as Doxil (pegylated 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. Food and Drug Administration (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>

===Popular culture===

Doxorubicin (under its brand name Adriamycin) is the subject of "Airplane Message", a strip of the webcomic ''xkcd''. The strip alludes to the drug's origins in "the dirt from an Italian castle", using this as an example of a "cool fact" that should be put on banners towed by light aircraft instead of conventional advertising.<ref>xkcd.com/1355</ref>

==Research==

Combination therapy experiments with sirolimus (rapamycin) and doxorubicin have shown promise in treating Akt-positive lymphomas 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 murine monoclonal antibody with doxorubicin created an immunoconjugate that was able to eliminate HIV-1 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 plasmepsin II, an enzyme unique to the malarial parasite ''Plasmodium falciparum''.<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 GlaxoSmithKline (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 theranostic 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 dielectric constant 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 == {{Reflist}}

== External links == * {{Commonscatinline}} * {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/doxorubicin | archive-url = https://web.archive.org/web/20160705113928/http://druginfo.nlm.nih.gov/drugportal/name/Doxorubicin | url-status = dead | archive-date = 5 July 2016 | publisher = U.S. National Library of Medicine| work = Drug Information Portal | title = Doxorubicin }} * {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/doxorubicin%20hydrochloride | archive-url = https://web.archive.org/web/20201023150657/https://druginfo.nlm.nih.gov/drugportal/name/doxorubicin%20hydrochloride | url-status = dead | archive-date = 23 October 2020 | publisher = U.S. National Library of Medicine| work = Drug Information Portal | title = Doxorubicin hydrochloride }}

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