anthracycline

{{multiple image

| align =

| direction = vertical

| width = 200

| image1 = Daunorubicin2DACS.svg

| caption1 = Daunorubicin, the prototypical anthracycline. Used against: Acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and Kaposi's sarcoma

| image2 = Doxorubicin.svg

| caption2 = Doxorubicin. Used against: Breast, lung, ovarian, liver and thyroid carcinomas, leukemias and lymphomas

| image3 = Epirubicin.svg

| caption3 = Epirubicin. Used against: Breast, ovarian, gastric, lung cancers, and lymphomas

| image4 = Idarubicin.svg

| caption4 = Idarubicin. Used against: Acute myeloid leukemia (AML)

}}

{{See also|Doxorubicin#History|Daunorubicin#History|History of cancer chemotherapy}}

Daunorubicin is a red pigmented drug which was discovered in the early 1960s. It was isolated from a strain of Streptomyces peucetius by A. Di Marco and coworkers, working for Farmitalia Research Laboratories in Italy who called it daunomycin.{{cite journal | vauthors = Dimarco A, Gaetani M, Orezzi P, Scarpinato BM, Silvestrini R, Soldati M, Dasdia T, Valentini L | title = 'Daunomycin', a new antibiotic of the rhodomycin group | journal = Nature | volume = 201 | issue = 4920 | pages = 706–7 | date = February 1964 | pmid = 14142092 | doi = 10.1038/201706a0 | bibcode = 1964Natur.201..706D | s2cid = 4292271 }} About the same time Dubost and coworkers in France also discovered the compound and named it rubidomycin.{{cite journal | vauthors = Dubost M, Ganter P, Maral R, Ninet L, Pinnert S, Preudhomme J, Werner GH | title = Rubidomycin: a new antibiotic with cytostatic properties | journal = Cancer Chemotherapy Reports | volume = 41 | pages = 35–6 | date = September 1964 | pmid = 14213139 }} Daunorubicin was adopted as the international name. Initially it was seen to have activity against murine tumours and then in clinical trials it was found to be active against leukaemia and lymphomas.

Doxorubicin was isolated from a mutated variant of S. peucetius (var. caesius). It differs from daunorubicin only by the addition of a hydroxyl group at the carbon 14 position. This modification greatly changes the activity of the drug making it highly effective against a wide range of solid tumours, leukaemia and lymphomas. It is the standard by which novel anthracyclines are judged.{{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 = 1101–10 | date = November 1969 | pmid = 5365804 | doi = 10.1002/bit.260110607 | s2cid = 21897153 }}{{cite journal | vauthors = Blum RH, Carter SK | title = Adriamycin. A new anticancer drug with significant clinical activity | journal = Annals of Internal Medicine | volume = 80 | issue = 2 | pages = 249–59 | date = February 1974 | pmid = 4590654 | doi = 10.7326/0003-4819-80-2-249 }}{{Cite book|title=Cancer management in man : chemotherapy, biological therapy, hyperthermia and supporting measures|date=2011|publisher=Springer|others=Minev, Boris R.|isbn=9789048197040|location=Dordrecht|oclc=704395391}}{{Cite book|title=DeVita, Hellman, and Rosenberg's cancer : principles & practice of oncology|date=2008|publisher=Wolters Kluwer/Lippincott Williams & Wilkins|others=DeVita, Vincent T., Jr., 1935-, Lawrence, Theodore S., Rosenberg, Steven A.|isbn=9780781772075|edition=8th|location=Philadelphia|oclc=192027662}}{{cite journal | vauthors = Takemura G, Fujiwara H | title = Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management | journal = Progress in Cardiovascular Diseases | volume = 49 | issue = 5 | pages = 330–52 | date = March 2007 | pmid = 17329180 | doi = 10.1016/j.pcad.2006.10.002 }}

The first anthracyclines were so successful that thousands of analogues have been produced in attempts to find compounds with improved therapeutic applications. Only epirubicin and idarubicin have been adopted for worldwide use. Epirubicin has similar activity to doxorubicin, however has reduced cardiotoxic side effects.{{cite journal | vauthors = Arcamone F, Penco S, Vigevani A | date = 1975 | title = Adriamycin (NSC 123127): new chemical developments and analogs. | journal = Cancer Chemotherapy Reports | volume = 6 | pages = 123–129 }} Idarubicin is a fat soluble variant of daunorubicin and is orally bioavailable.{{cite journal | vauthors = Arcamone F, Bernardi L, Giardino P, Patelli B, Di Marco A, Casazza AM, Pratesi G, Reggiani P | title = Synthesis and antitumor activity of 4-demethoxydaunorubicin, 4-demethoxy-7,9-diepidaunorubicin, and their beta anomers | journal = Cancer Treatment Reports | volume = 60 | issue = 7 | pages = 829–34 | date = July 1976 | pmid = 1009518 }}

Several groups of researchers focused on designing compounds that retained the polycyclic aromatic chromophore of the anthracyclines (favouring intercalation into DNA) and substituting the sugar residue with simple side chains. This led to the identification of the mitoxantrone which is classed as an anthracenedione compound and is used in the clinic for the management of various cancers.{{cite journal | vauthors = Evison BJ, Sleebs BE, Watson KG, Phillips DR, Cutts SM | title = Mitoxantrone, More than Just Another Topoisomerase II Poison | journal = Medicinal Research Reviews | volume = 36 | issue = 2 | pages = 248–99 | date = March 2016 | pmid = 26286294 | doi = 10.1002/med.21364 | s2cid = 8973790 }} Disaccharide analogues have been shown to retain anticancer activity, and are being further investigated with respect to their mechanism of action.{{cite journal | vauthors = Marinello J, Delcuratolo M, Capranico G | title = Anthracyclines as Topoisomerase II Poisons: From Early Studies to New Perspectives | journal = International Journal of Molecular Sciences | volume = 19 | issue = 11 | pages = 3480 | date = November 2018 | pmid = 30404148 | pmc = 6275052 | doi = 10.3390/ijms19113480 | doi-access = free }}

Although it has been 50 years from the discovery of anthracyclines, and despite recent advances in the development of targeted therapies for cancers, around 32% of breast cancer patients, 57%-70% of elderly lymphoma patients and 50–60% of childhood cancer patients are treated with anthracyclines.{{cite journal | vauthors = McGowan JV, Chung R, Maulik A, Piotrowska I, Walker JM, Yellon DM | title = Anthracycline Chemotherapy and Cardiotoxicity | journal = Cardiovascular Drugs and Therapy | volume = 31 | issue = 1 | pages = 63–75 | date = February 2017 | pmid = 28185035 | pmc = 5346598 | doi = 10.1007/s10557-016-6711-0 }} Some cancers benefit from neoadjuvant anthracycline-based regimes, and these include triple negative breast cancers that do not respond well to targeted therapies due to the lack of available receptors that can be targeted.{{cite journal | vauthors = Wahba HA, El-Hadaad HA | title = Current approaches in treatment of triple-negative breast cancer | journal = Cancer Biology & Medicine | volume = 12 | issue = 2 | pages = 106–16 | date = June 2015 | pmid = 26175926 | pmc = 4493381 | doi = 10.7497/j.issn.2095-3941.2015.0030 | doi-broken-date = 1 November 2024 }} Compared to non-triple negative breast cancer patients, triple negative breast cancer patients have shown better response rate and higher pathological response rate with anthracycline use, an indicator used for predicting improved long-term outcomes.

Anthracyclines remain some of the most widely used chemotherapeutic agents but their potential is limited by its dose-limiting toxicities. Currently, there are many studies being conducted in the search for anthracyclines with better anti-tumour efficacy or with reduced side effects using different nanotechnology-based drug delivery systems.{{cite journal | vauthors = Cagel M, Grotz E, Bernabeu E, Moretton MA, Chiappetta DA | title = Doxorubicin: nanotechnological overviews from bench to bedside | journal = Drug Discovery Today | volume = 22 | issue = 2 | pages = 270–281 | date = February 2017 | pmid = 27890669 | doi = 10.1016/j.drudis.2016.11.005 | hdl = 11336/47838 | hdl-access = free }}{{cite journal | vauthors = Poon RT, Borys N | title = Lyso-thermosensitive liposomal doxorubicin: a novel approach to enhance efficacy of thermal ablation of liver cancer | journal = Expert Opinion on Pharmacotherapy | volume = 10 | issue = 2 | pages = 333–43 | date = February 2009 | pmid = 19236203 | doi = 10.1517/14656560802677874 | s2cid = 73112213 }}{{cite journal | vauthors = Mukai H, Kogawa T, Matsubara N, Naito Y, Sasaki M, Hosono A | title = A first-in-human Phase 1 study of epirubicin-conjugated polymer micelles (K-912/NC-6300) in patients with advanced or recurrent solid tumors | journal = Investigational New Drugs | volume = 35 | issue = 3 | pages = 307–314 | date = June 2017 | pmid = 28054329 | doi = 10.1007/s10637-016-0422-z | s2cid = 596267 }}{{cite journal | vauthors = Nishiyama N, Matsumura Y, Kataoka K | title = Development of polymeric micelles for targeting intractable cancers | journal = Cancer Science | volume = 107 | issue = 7 | pages = 867–74 | date = July 2016 | pmid = 27116635 | pmc = 4946707 | doi = 10.1111/cas.12960 }}

file:Doxorubicin localisation.jpg. Localisation of doxorubicin (red) in the nuclei of MCF-7_cc10 cells. Green fluorescence represents lysosome.{{cite journal | vauthors = Guo B, Tam A, Santi SA, Parissenti AM | title = Role of autophagy and lysosomal drug sequestration in acquired resistance to doxorubicin in MCF-7 cells | journal = BMC Cancer | volume = 16 | issue = 1 | pages = 762 | date = September 2016 | pmid = 27687594 | pmc = 5043608 | doi = 10.1186/s12885-016-2790-3 | doi-access = free }}|alt=|left]]

The anthracyclines have been widely studied for their interactions with cellular components and impact on cellular processes. This includes studies in cultured cells and in whole animal systems. A myriad of drug-cellular interactions have been documented in the scientific literature and these vary with respect to the properties of target cells, drug dose and drug intermediates produced. Since artefactual mechanisms of action can be observed,{{cite journal | vauthors = Gewirtz DA | title = A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin | journal = Biochemical Pharmacology | volume = 57 | issue = 7 | pages = 727–41 | date = April 1999 | pmid = 10075079 | doi = 10.1016/S0006-2952(98)00307-4 }} the following mechanisms which occur at clinically relevant drug concentrations are the most important.

Anthracyclines are readily taken up by cells and localised to the nucleus. The chromophore moiety of anthracyclines has intercalating function and inserts in between the adjacent base pair of DNA. The intercalating function inhibits DNA and RNA synthesis in highly replicating cells, subsequently blocking the transcription and replication processes.

This is by far the most-accepted mechanism to explain the action of anthracyclines as topoisomerase-II mediated toxicity is evident at clinically relevant drug concentrations. Topoisomerase-II is an enzyme that creates temporary double-stranded DNA (dsDNA) breaks and reseals them after managing torsion of DNA supercoils. Anthracyclines intercalated into DNA, form a stable anthracycline-DNA-topoisomerase II ternary complex thus "poisoning" the enzyme and impeding the religation of double-stranded DNA breaks.{{cite journal | vauthors = Binaschi M, Bigioni M, Cipollone A, Rossi C, Goso C, Maggi CA, Capranico G, Animati F | title = Anthracyclines: selected new developments | journal = Current Medicinal Chemistry. Anti-Cancer Agents | volume = 1 | issue = 2 | pages = 113–30 | date = August 2001 | pmid = 12678762 | doi = 10.2174/1568011013354723 }} This topoisomerase-II-mediated DNA damage subsequently promotes growth arrest and recruits DNA repair machinery. When the repair process fails, the lesions initiate programmed cell death.

The quinone moiety of anthracyclines can undergo redox reactions to generate excessive reactive oxygen species (ROS) in the presence of oxidoreductive enzymes such as cytochrome P450 reductase, NADH dehydrogenase and xanthine oxidase. Converting quinone to semiquinone produces free radicals that actively react with oxygen to generate superoxides, hydroxyl radicals and peroxides.{{cite journal | vauthors = Angsutararux P, Luanpitpong S, Issaragrisil S | title = Chemotherapy-Induced Cardiotoxicity: Overview of the Roles of Oxidative Stress | journal = Oxidative Medicine and Cellular Longevity | volume = 2015 | pages = 795602 | date = 2015 | pmid = 26491536 | pmc = 4602327 | doi = 10.1155/2015/795602 | doi-access = free }}{{cite journal | vauthors = Simůnek T, Stérba M, Popelová O, Adamcová M, Hrdina R, Gersl V | title = Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron | journal = Pharmacological Reports | volume = 61 | issue = 1 | pages = 154–71 | date = January 2009 | pmid = 19307704 | doi = 10.1016/S1734-1140(09)70018-0 | s2cid = 4728513 }} In addition, the availability of cellular iron catalyses redox reactions and further generates ROS. The excessive ROS that cannot be detoxified results in oxidative stress, DNA damage, and lipid peroxidation thereby triggering apoptosis.

Anthracyclines can also form adducts with DNA by a single covalent bond through an aminal linkage from the 3’-amino of daunosamine to the exocyclic amino of guanine.{{cite journal | vauthors = Cutts SM, Rephaeli A, Nudelman A, Ugarenko M, Phillips DR | title = Potential Therapeutic Advantages of Doxorubicin when Activated by Formaldehyde to Function as a DNA Adduct-Forming Agent | journal = Current Topics in Medicinal Chemistry | volume = 15 | issue = 14 | pages = 1409–22 | date = 2015 | pmid = 25866273 | doi = 10.2174/1568026615666150413154512 }} The supply of extracellular formaldehyde using formaldehyde-releasing prodrugs can promote covalent DNA adduct formation. Such adducts have been shown to block GpC specific transcription factors and induce apoptotic responses.{{cite journal | vauthors = Cutts SM, Nudelman A, Rephaeli A, Phillips DR | title = The power and potential of doxorubicin-DNA adducts | journal = IUBMB Life | volume = 57 | issue = 2 | pages = 73–81 | date = February 2005 | pmid = 16036566 | doi = 10.1080/15216540500079093 | s2cid = 6784020 }}

Results from a recent meta-analysis provide evidence that breast cancer patients with either duplication of centromere 17 or aberrations in TOP2A, the gene coding for topoisomerase-IIα, benefit from adjuvant chemotherapy that incorporates anthracyclines.{{cite journal | vauthors = Bartlett JM, McConkey CC, Munro AF, Desmedt C, Dunn JA, Larsimont DP, O'Malley FP, Cameron DA, Earl HM, Poole CJ, Shepherd LE, Cardoso F, Jensen MB, Caldas C, Twelves CJ, Rea DW, Ejlertsen B, Di Leo A, Pritchard KI | display-authors = 6 | title = Predicting Anthracycline Benefit: TOP2A and CEP17-Not Only but Also | journal = Journal of Clinical Oncology | volume = 33 | issue = 15 | pages = 1680–7 | date = May 2015 | pmid = 25897160 | doi = 10.1200/JCO.2013.54.7869 | doi-access = free }} This does not include subgroups of patients that harbour amplification of HER2. The observations from this study also allow patients to be identified where anthracyclines might be safely omitted from treatment strategies.

Anthracycline administration is often accompanied by adverse drug reactions that limit the use of anthracyclines in the clinics. Two major dose limiting toxicities of anthracyclines include myelosuppression and cardiotoxicity. Fortunately, the introduction of therapeutic cytokines allows management of myelosuppression. Hence, cardiac injury remains as the major drawback of anthracycline-based anti-cancer agents. Cardiotoxicity in patients and mice can be mitigated by circulating hemopexin.{{cite journal|author1=Jing Liu|author2=Sarah Lane|title=Circulating hemopexin modulates anthracycline cardiac toxicity in patients and in mice|journal=Science Advances|volume=8|issue=51|date=December 23, 2022|pages=eadc9245 |doi=10.1126/sciadv.adc9245|pmid=36563141|pmc=9788780|bibcode=2022SciA....8C9245L }} (research conducted on patients affected by breast cancer).

Anthracycline-mediated cardiotoxicity is dose-dependent and cumulative, with the damage imposed to heart occurring upon the very first dose and then accumulating with each anthracycline cycle. There are four types of anthracycline-associated cardiotoxicity that have been described.

In the clinic, a maximum recommended cumulative dose is set for anthracyclines to prevent the development of congestive heart failure.{{cite journal | vauthors = Ewer MS, Ewer SM | title = Cardiotoxicity of anticancer treatments | journal = Nature Reviews. Cardiology | volume = 12 | issue = 9 | pages = 547–58 | date = September 2015 | pmid = 25962976 | doi = 10.1038/nrcardio.2015.65 | s2cid = 9317756 }} As an example, the incidence of congestive heart failure is 4.7%, 26% and 48% respectively when patients received doxorubicin at 400 mg/m², 550 mg/m² and 700 mg/m². Therefore, the lifetime cumulative doxorubicin exposure is limited to 400–450 mg/m² in order to reduce congestive heart failure incidence to less than 5%, although variation in terms of tolerance to doxorubicin exists between individuals. The risk factors that influence the extent of cardiac injury caused by anthracyclines include genetic variability, age (low or high age groups), previous treatments with cardiotoxic drugs and history of cardiac diseases. Children are particularly at risk due to the anthracycline activity that can compromise the development of the immature heart.

Cardiac injury that occurs in response to initial doses of anthracycline can be detected by a rise in troponin level immediately after administration. Biopsy also allows early detection of cardiac injury by evaluating heart ultrastructure changes. Receiving cumulative doses of anthracycline causes left ventricle dysfunction and with continued dosage reaches a certain threshold that can be clinically detected by non-invasive techniques such as 2D echocardiography and strain rate imaging. Advances in developing more sensitive imaging techniques and biomarkers allow early detection of cardiotoxicity and allow cardioprotective intervention to prevent anthracycline-mediated cardiotoxicity.

The predominant susceptibility of the heart to anthracyclines is due in part to a preferential mitochondrial localisation of anthracyclines. This is attributed to high affinity interaction between anthracyclines and cardiolipin, a phospholipid present in the heart mitochondrial membrane, as heart tissue contains a relatively high number of mitochondria per cell. Heart tissue also has an impaired defence against oxidative stress, displaying a low level of anti-oxidant enzymes such as catalase and superoxide dismutase for detoxifying anthracycline-mediated ROS.

The mechanisms accounting for anthracycline-induced cardiac damage are complex and interrelated. It was first recognised to be related to the oxidative stress induced by anthracyclines. A more recent explanation has emerged, in which anthracycline-mediated cardiotoxicity is due to anthracycline-topoisomerase IIb poisoning, leading to downstream oxidative stress.{{cite journal | vauthors = Vejpongsa P, Yeh ET | title = Topoisomerase 2β: a promising molecular target for primary prevention of anthracycline-induced cardiotoxicity | journal = Clinical Pharmacology and Therapeutics | volume = 95 | issue = 1 | pages = 45–52 | date = January 2014 | pmid = 24091715 | doi = 10.1038/clpt.2013.201 | s2cid = 565837 }}

In order to reduce the impact of cardiac injury in response to anthracyclines, a few cardioprotective strategies have been explored. Liposomal formulations of anthracyclines (discussed below) have been developed and used to reduce cardiac damage.{{cite journal | vauthors = Gabizon A, Shmeeda H, Barenholz Y | title = Pharmacokinetics of pegylated liposomal Doxorubicin: review of animal and human studies | journal = Clinical Pharmacokinetics | volume = 42 | issue = 5 | pages = 419–36 | date = 2003 | pmid = 12739982 | doi = 10.2165/00003088-200342050-00002 | s2cid = 29494837 }} Other novel anthracycline analogues such as epirubicin and idarubicin also provide options to reduce adverse cardiac events; these analogues have failed to show superior anti-cancer activity to the parent compounds. An alternative drug administration method involving continuous infusion for 72 h as compared to bolus administration provides some protection and can be used when high cumulative doses are anticipated.

When anthracyclines are given intravenously, it may result in accidental extravasation at injection sites. It is estimated that the extravasation incidence ranges from 0.1% to 6%.{{cite journal | vauthors = Jordan K, Behlendorf T, Mueller F, Schmoll HJ | title = Anthracycline extravasation injuries: management with dexrazoxane | journal = Therapeutics and Clinical Risk Management | volume = 5 | issue = 2 | pages = 361–6 | date = April 2009 | pmid = 19536310 | pmc = 2697522 | doi = 10.2147/tcrm.s3694 | doi-access = free }} Extravasation causes serious complications to surrounding tissues with the symptoms of tissue necrosis and skin ulceration. Dexrazoxane is primarily used to treat anthracyclines post-extravasation by acting as a topoisomerase II inhibitor as well as a chelating agent to reduce oxidative stress caused by anthracyclines. Dexrazoxane has also been used with success as a cardioprotective compound in combination with doxorubicin in metastatic breast cancer patients who have been treated with more than 300 mg/m² doxorubicin, as well as in patients who are anticipated to have a beneficial effect from high cumulative doses of doxorubicin.{{cite journal | vauthors = Chou H, Lin H, Liu JM | title = A tale of the two PEGylated liposomal doxorubicins | journal = OncoTargets and Therapy | volume = 8 | pages = 1719–20 | date = 2015-07-13 | pmid = 26203262 | pmc = 4508070 | doi = 10.2147/OTT.S79089 | doi-access = free }}

There is no high quality evidence to confirm if cardioprotective treatments are effective.{{cite journal | vauthors = van Dalen EC, Caron HN, Dickinson HO, Kremer LC | title = Cardioprotective interventions for cancer patients receiving anthracyclines | journal = The Cochrane Database of Systematic Reviews | issue = 6 | pages = CD003917 | date = June 2011 | volume = 2016 | pmid = 21678342 | pmc = 6457676 | doi = 10.1002/14651858.cd003917.pub4 }} Studies of the cardioprotective nature of dexrazoxane, provide evidence that it can prevent heart damage without interfering with the anti-tumour effects of anthracycline treatment. Patients given dexrazoxane with their anthracycline treatment had their risk of heart failure reduced compared to those treated with anthracyclines without dexrazoxane. There was no effect on survival though.

Radiolabelled doxorubicin has been utilised as a breast cancer lesion imaging agent in a pilot study. This radiochemical, ^99mTc-doxorubicin, localised to mammary tumour lesions in female patients, and is a potential radiopharmaceutical for imaging of breast tumours.{{cite journal | vauthors = Araujo FI, Proença FP, Ferreira CG, Ventilari SC, Rosado de Castro PH, Moreira RD, Fonseca LM, Souza SA, Gutfilen B | title = Use of (99m)Tc-doxorubicin scintigraphy in females with breast cancer: a pilot study | journal = The British Journal of Radiology | volume = 88 | issue = 1052 | pages = 20150268 | date = August 2015 | pmid = 26111270 | pmc = 4651371 | doi = 10.1259/bjr.20150268 }}

In some cases, anthracyclines may be ineffective due to the development of drug resistance. It can either be primary resistance (insensitive response to initial therapy) or acquired resistance (present after demonstrating complete or partial response to treatment).{{cite journal | vauthors = Perez EA | title = Impact, mechanisms, and novel chemotherapy strategies for overcoming resistance to anthracyclines and taxanes in metastatic breast cancer | journal = Breast Cancer Research and Treatment | volume = 114 | issue = 2 | pages = 195–201 | date = March 2009 | pmid = 18443902 | doi = 10.1007/s10549-008-0005-6 | s2cid = 7302079 }} Resistance to anthracyclines involves many factors, but it is often related to overexpression of the transmembrane drug efflux protein P-glycoprotein (P-gp) or multidrug resistance protein 1 (MRP1), which removes anthracyclines from cancer cells.{{cite journal | vauthors = Arnason T, Harkness T | title = Development, Maintenance, and Reversal of Multiple Drug Resistance: At the Crossroads of TFPI1, ABC Transporters, and HIF1 | journal = Cancers | volume = 7 | issue = 4 | pages = 2063–82 | date = October 2015 | pmid = 26501324 | pmc = 4695877 | doi = 10.3390/cancers7040877 | doi-access = free }} A large research effort has been focused in designing inhibitors against MRP1 to re-sensitise anthracycline resistant cells, but many such drugs have failed during clinical trials.

{{multiple_image|image1=Liposomal dox schematic drawing.jpg|caption1=Schematic representation of pegylated liposomal doxorubicin|image2=Doxil Cryo-TEM.jpg|caption2=Cryo-TEM images of Doxil (pegylated liposomal doxorubicin){{Cite journal| vauthors = Fan Y, Zhang Q |date= April 2013 |title=Development of liposomal formulations: From concept to clinical investigations |journal=Asian Journal of Pharmaceutical Sciences|volume=8|issue=2|pages=81–87|doi=10.1016/j.ajps.2013.07.010 |doi-access=free}}|size2=140px|direction=vertical

}}

Liposomes are spherical shape, phospholipid vesicles that can be formed with one or more lipid bilayers with phospholipids or cholesterols.{{cite journal | vauthors = Sercombe L, Veerati T, Moheimani F, Wu SY, Sood AK, Hua S | title = Advances and Challenges of Liposome Assisted Drug Delivery | journal = Frontiers in Pharmacology | volume = 6 | pages = 286 | date = 2015-12-01 | pmid = 26648870 | pmc = 4664963 | doi = 10.3389/fphar.2015.00286 | doi-access = free }} The ability of liposomes to encapsulate both hydrophobic and hydrophilic drug compounds allowed liposomes to be an efficient drug delivery systems (DDS) to deliver a range of drugs in these nano-carriers.

Liposomal formulations of anthracyclines have been developed to maintain or even enhance the therapeutic efficacy of anthracyclines while reduce its limiting toxicities to healthy tissues, particularly cardiotoxicity. Currently, there are two liposomal formulations of doxorubicin available in the clinics.

Doxil/Caelyx is the first FDA approved liposomal DDS, and was initially used to treat AIDS-related Kaposi’s sarcoma in 1995 and is now being used for treating recurrent ovarian cancer, metastatic breast cancer with increased cardiac risk, and multiple myeloma.{{cite journal | vauthors = Barenholz Y | title = Doxil®--the first FDA-approved nano-drug: lessons learned | journal = Journal of Controlled Release | volume = 160 | issue = 2 | pages = 117–34 | date = June 2012 | pmid = 22484195 | doi = 10.1016/j.jconrel.2012.03.020 }}{{cite journal | vauthors = Udhrain A, Skubitz KM, Northfelt DW | title = Pegylated liposomal doxorubicin in the treatment of AIDS-related Kaposi's sarcoma | journal = International Journal of Nanomedicine | volume = 2 | issue = 3 | pages = 345–52 | date = 2007 | pmid = 18019833 | pmc = 2676669 }} Doxorubicin is encapsulated in a nano-carrier known as Stealth or sterically stabilised liposomes, consisting of unilamellar liposomes coated with hydrophilic polymer polyethylene glycol (PEG) that is covalently linked to liposome phospholipids.{{cite journal | vauthors = Soloman R, Gabizon AA | title = Clinical pharmacology of liposomal anthracyclines: focus on pegylated liposomal Doxorubicin | journal = Clinical Lymphoma & Myeloma | volume = 8 | issue = 1 | pages = 21–32 | date = February 2008 | pmid = 18501085 | doi = 10.3816/CLM.2008.n.001 }} The PEG coating serves as a barrier from opsonisation, rapid clearance while the drug is stably retained inside the nano-carriers via an ammonium sulphate chemical gradient.{{cite journal | vauthors = Haran G, Cohen R, Bar LK, Barenholz Y | title = Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1151 | issue = 2 | pages = 201–15 | date = September 1993 | pmid = 8373796 | doi = 10.1016/0005-2736(93)90105-9 }} A major advantage of using nano-carriers as a drug delivery system is the ability of the nano-carriers to utilise the leaky vasculature of tumours and their impaired lymphatic drainage via the EPR effect.{{cite journal | vauthors = Maeda H, Nakamura H, Fang J | title = The EPR effect for macromolecular drug delivery to solid tumors: Improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo | journal = Advanced Drug Delivery Reviews | volume = 65 | issue = 1 | pages = 71–9 | date = January 2013 | pmid = 23088862 | doi = 10.1016/j.addr.2012.10.002 }}

The maximum plasma concentration of free doxorubicin after Doxil administration is substantially lower compared to conventional doxorubicin, providing an explanation for its low cardiotoxicity profile. However, Doxil can cause Palmar-plantar erythrodysesthesia (PPE, hand and foot syndrome) due to its accumulation in the skin. Doxil has lower maximum tolerable dose (MTD) at 50 mg/m² every 4 weeks compared to free doxorubicin at 60 mg/m² every 3 weeks. Despite this, the maximum cumulative dose for Doxil is still higher compared to doxorubicin due to its cardioprotective characteristics.

Myocet is another non-pegylated liposome encapsulated doxorubicin citrate complex approved for use in combination with cyclophosphamide in metastatic breast cancer patients as first line treatment in Europe and Canada. Doxorubicin is loaded into the liposomes just before administration to patients with a maximum single dose of 75 mg/m² every 3 weeks. Myocet has similar efficacy as conventional doxorubicin, while significantly reducing cardiac toxicity.{{cite journal | vauthors = Batist G | title = Cardiac safety of liposomal anthracyclines | journal = Cardiovascular Toxicology | volume = 7 | issue = 2 | pages = 72–4 | date = 2007 | pmid = 17652807 | doi = 10.1007/s12012-007-0014-4 | citeseerx = 10.1.1.529.9071 | s2cid = 2815965 }}{{cite journal | vauthors = Batist G, Barton J, Chaikin P, Swenson C, Welles L | title = Myocet (liposome-encapsulated doxorubicin citrate): a new approach in breast cancer therapy | journal = Expert Opinion on Pharmacotherapy | volume = 3 | issue = 12 | pages = 1739–51 | date = December 2002 | pmid = 12472371 | doi = 10.1517/14656566.3.12.1739 | s2cid = 46242391 }}{{cite journal | vauthors = Leonard RC, Williams S, Tulpule A, Levine AM, Oliveros S | title = Improving the therapeutic index of anthracycline chemotherapy: focus on liposomal doxorubicin (Myocet) | journal = Breast | volume = 18 | issue = 4 | pages = 218–24 | date = August 2009 | pmid = 19656681 | doi = 10.1016/j.breast.2009.05.004 | doi-access = free }}

Drug interactions with anthracyclines can be complex and might be due to the effect, side effects, or metabolism of the anthracycline. Drugs which inhibit Cytochrome P450 or other oxidases may reduce clearance of anthracyclines, prolonging their circulating half-life which can increase cardiotoxicity and other side effects.{{cite journal | vauthors = Kivistö KT, Kroemer HK, Eichelbaum M | title = The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug interactions | journal = British Journal of Clinical Pharmacology | volume = 40 | issue = 6 | pages = 523–30 | date = December 1995 | pmid = 8703657 | pmc = 1365206 | doi = 10.1111/j.1365-2125.1995.tb05796.x }} As they act as antibiotics anthracyclines can reduce the effectiveness of live culture treatments such as Bacillus Calmette-Guerin therapy for bladder cancer.{{cite web | publisher = Bedford Laboratories | date = 2012 | title = Product Information: Adriamcycin (Doxorubcin HCl) for Injection, USP. In (pp. 8). | location = Ohio | url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/062921s022lbl.pdf }} As they act as myelosuppressors anthracyclines can reduce the effectiveness of vaccines by inhibiting the immune system.{{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 = 157–70 | date = February 2013 | pmid = 23278683 | doi = 10.1111/j.2042-7158.2012.01567.x | s2cid = 34737360 | doi-access = free }}

Several interactions are of particular clinical importance. Though dexrazoxane can be used to mitigate cardiotoxicity or extravasation damage of anthracyclines it also may reduce their effectiveness and the recommendation is not to start dexrazoxane treatment upon initial anthracycline treatment.{{cite journal | vauthors = Lyu YL, Kerrigan JE, Lin CP, Azarova AM, Tsai YC, Ban Y, Liu LF|author7-link=Leroy Liu | title = Topoisomerase IIbeta mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane | journal = Cancer Research | volume = 67 | issue = 18 | pages = 8839–46 | date = September 2007 | pmid = 17875725 | doi = 10.1158/0008-5472.CAN-07-1649 | doi-access = }} Trastuzumab (a HER2 antibody used to treat breast cancer) may enhance the cardiotoxicity of anthracyclines{{cite journal | vauthors = Ewer MS, Ewer SM | title = Troponin I provides insight into cardiotoxicity and the anthracycline-trastuzumab interaction | journal = Journal of Clinical Oncology | volume = 28 | issue = 25 | pages = 3901–4 | date = September 2010 | pmid = 20679626 | doi = 10.1200/JCO.2010.30.6274 | doi-access = free }}{{cite journal | vauthors = Rayson D, Richel D, Chia S, Jackisch C, van der Vegt S, Suter T | title = Anthracycline-trastuzumab regimens for HER2/neu-overexpressing breast cancer: current experience and future strategies | journal = Annals of Oncology | volume = 19 | issue = 9 | pages = 1530–9 | date = September 2008 | pmid = 18480068 | doi = 10.1093/annonc/mdn292 | doi-access = free }} although the interaction can be minimised by implementing a time interval between anthracycline and trastuzumab administration.{{cite journal | vauthors = Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L | title = Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2 | journal = The New England Journal of Medicine | volume = 344 | issue = 11 | pages = 783–92 | date = March 2001 | pmid = 11248153 | doi = 10.1056/NEJM200103153441101 | doi-access = free }} Taxanes (except docetaxel) may decrease anthracycline metabolism, increasing serum concentrations of anthracyclines.{{cite journal | vauthors = Gianni L, Viganò L, Locatelli A, Capri G, Giani A, Tarenzi E, Bonadonna G | title = Human pharmacokinetic characterization and in vitro study of the interaction between doxorubicin and paclitaxel in patients with breast cancer | journal = Journal of Clinical Oncology | volume = 15 | issue = 5 | pages = 1906–15 | date = May 1997 | pmid = 9164201 | doi = 10.1200/JCO.1997.15.5.1906 }} The recommendation is to treat with anthracyclines first if combination treatment with taxanes is required.

• Anthraquinone
• Polymer-drug conjugates

{{Academic peer reviewed|Q=Q60638523|doi-access=free}}

{{reflist}}

{{Notelist}}

• {{commons category-inline|Anthracyclines}}

{{Chemotherapeutic agents}}

{{Authority control}}