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Article information

Authors: Alison Cheong[i][a], Sean McGrath[i][a], Suzanne Cutts[a][ii]  

See author information ▼
  1. ↑ 1.0 1.1 1.2 La Trobe University, Melbourne, Australia
  1. ↑ 1.0 1.1 contributed equally to the work
  2. ↑ s.cutts@latrobe.edu.au

Abstract

Anthracyclines are a clinically important class of antineoplastic agents used to treat a wide variety of solid and blood cancers. The first described anthracycline, daunorubicin, was first isolated from a strain of Streptomyces peucetius in the early 1960s. Clinically the most widely used are doxorubicin, daunorubicin and their semi-synthetic derivatives epirubicin and idarubicin. They primarily act by intercalating with DNA and inhibiting topoisomerase II, resulting in DNA breaks and abrogated DNA synthesis. The most serious side effect of anthracycline use is cumulative dose-dependent cardiotoxicity, limiting recommended maximum lifetime treatment to 400-450 mg/m2. Several liposomal formulations of doxorubicin are in use, having the benefits of prolonging retention rate while reducing peak plasma concentration of free drug. Several clinical trials of anthracycline-loaded nanoparticles are currently underway.

Non-technical summary
Anthracyclines are an important class of chemotherapy drugs used to treat a wide variety of solid and blood cancers. The most important clinically are doxorubicin and daunorubicin. They act to inhibit cellular processes around DNA metabolism which results in the death of rapidly dividing cells. Most anthracyclines are administered directly into the blood. Common side effects include decreased immune cell production, nausea, vomiting and hair loss. The greatest potential side effect is dose related damage to heart tissue and modern treatment regimens are designed to minimise this risk. Research continues around new anthracycline variants and formulation with several clinical trials currently underway around the world.

Introduction

Anthracyclines are a class of chemotherapy drugs used for the treatment of cancer. They are used to treat a broad range of solid and blood cancers. Clinically the most important anthracyclines are doxorubicin, daunorubicin, epirubicin and idarubicin (Table 1). The drugs act mainly by intercalating with DNA and interfering with DNA metabolism and RNA production. Cytotoxicity is primarily due to inhibition of topoisomerase II after the enzyme induces a break in DNA, preventing religation of the break and leading to cell death.

The basic structure of anthracyclines is that of a tetracyclic molecule with an anthraquinone backbone connected to a sugar moiety by a glycosidic linkage. When taken up by a cell the four ring structure intercalates between DNA bases pairs while the sugar sits within the minor groove and interacts with adjacent base pairs.[1]

History

 Doxorubicin as an intercalating agent. Two doxorubicin molecules intercalated within DNA.[2]


F. Vasconcellos, public domain, from PDB: 1D12.

Daunorubicin is a red pigmented drug which was discovered in the early 1960s. It was isolated from a strain of Streptomyces peucetius by Di Marco and coworkers, working for Farmitalia Research Laboratories in Italy who called it daunomycin.[3] About the same time Dubost and coworkers in France also discovered the compound and named it rubidomycin.[1] Daunorubicin was adopted as the international name.[4] 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 (Figure 1) 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.[5][6][7][8][9]

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.[10] Idarubicin is a fat soluble variant of daunorubicin and is orally bioavailable.[4][11]

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.[12] Disaccharide analogues have been shown to retain anticancer activity, and are being further investigated with respect to their mechanism of action.[13]

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.[14] 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.[15] 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.[15]

Table 1. Clinically important Anthracyclines
Anthracycline Tradenames Activity
Daunorubicin

Daunomycin

Cerubidine

Acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and Kaposi's sarcoma
Doxorubicin

Adriamycin Breast, lung, ovarian, liver and thyroid carcinomas, leukemias and lymphomas
Epirubicin

Ellence (US)

Pharmorubicin

Breast, ovarian, gastric, lung cancers, and lymphomas
Idarubicin

Zavedos (UK)

Idamycin (USA)

Acute myeloid leukemia (AML)

Mechanism of Action

 Doxorubicin localisation to nuclei. Localisation of doxorubicin (red) in the nuclei of MCF-7cc10 cells. Green fluorescence represents lysosome.


Baoqing Guo et. al.,[16] CC-BY-4.0..

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, [17] the following mechanisms which occur at clinically relevant drug concentrations are the most important.  

DNA Intercalation

Anthracyclines are readily taken up by cells and localised to the nucleus (Figure 2). The chromophore moiety of anthracyclines has intercalating function and inserts in between the adjacent base pair of DNA (Figure 1).[17] The intercalating function inhibits DNA and RNA synthesis in highly replicating cells, subsequently blocking the transcription and replication processes.[17]

Topoisomerase-II poison

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.[13][17] 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.[18] 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.[19]

Reactive oxygen species

The quinone moiety of anthracyclines (Table 1) 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.[20][21] In addition, the availability of cellular iron catalyses redox reactions and further generates ROS.[20][21] The excessive ROS that cannot be detoxified results in oxidative stress, DNA damage, and lipid peroxidation thereby triggering apoptosis.[20][21]

DNA adduct formation

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.[22] 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.[22][23]

Clinical implications

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.[24] 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.[24]

Side Effects

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.[21][25] Hence, cardiac injury remains as the major drawback of anthracycline-based anti-cancer agents.

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 (Table 2).

Table 2. Anthracycline-mediated cardiotoxicity progression and symptoms[21][26]
Types of cardiotoxicity Time to presentation Symptoms
Acute During and immediately after drug administration Vasodilation, hypotension, transient cardiac rhythm disturbances
Subchronic 1-3 days post-drug administration Pericarditis-myocarditis
Early chronic Less than 1 year after completing anthracyclines treatment Dilated cardiomyopathy, restrictive cardiomyopathy (uncommon), left ventricular contractile dysfunction, congestive heart failure
Delayed/ late onset chronic More than 1 year after completing anthracyclines treatment Restrictive cardiomyopathy, dilated cardiomyopathy, congestive heart failure

In the clinic, a maximum recommended cumulative dose is set for anthracyclines to prevent the development of congestive heart failure.[27] 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.[14] 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.[27] 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.[21] Children are particularly at risk due to the anthracycline activity that can compromise the development of the immature heart.[27]

Cardiac injury that occurs in response to initial doses of anthracycline can be detected by a rise in troponin level immediately after administration.[27] Biopsy also allows early detection of cardiac injury by evaluating heart ultrastructure changes.[27] Receiving cumulative doses of anthracycline causes left ventricle dysfunction and with continued dosage reaches a certain threshold that can be clinically detected by non-evasive techniques such as 2D echocardiography and strain imaging. Advances in developing better sensitivity imaging techniques and biomarkers lead to early detection of cardiotoxicity and allow cardioprotective intervention to prevent anthracycline-mediated cardiotoxicity.[27]

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, and heart tissue contains a relatively high number of mitochondria per cell.[21] 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.[21]

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.[21] A more recent explanation has emerged where anthracycline-mediated cardiotoxicity is due to anthracycline-topoisomerase IIb poisoning, leading to downstream oxidative stress.[28]

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.[29] Other novel anthracyclines analogues such as epirubicin and idarubicin are also provide options to reduce adverse cardiac events, but these analogues have failed to show superior anti-cancer activity to the parent compounds.[19][27] An alternative drug administration method involving continuous infusion for 72 h as compared to bolus administration provides some protection and can be used in the clinics when high cumulative doses are anticipated.[27]

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%.[30] Extravasation causes serious complications to surrounding tissues with the symptoms of tissue necrosis and skin ulceration.[30] Dexrazoxane is primarily used to treat anthracyclines post-extravasation by acting as topoisomerase II inhibitor as well as a chelating agent to reduce oxidative stress caused by anthracyclines.[30] 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 patients who are anticipated to have a beneficial effect from high cumulative doses of doxorubicin.[31][29]

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 in patients.[32]

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).[33] 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) that removes anthracyclines from cancer cells.[34][33] A large research effort has been focused in designing inhibitors against MRP1 to re-sensitise anthracyclines resistant cells but many have failed during clinical trials.[34]

Liposomal-based clinical formulations

A

B
 A) Schematic representation of pegylated liposomal doxorubicin.

B) Cryo-TEM images of Doxil (pegylated liposomal doxorubicin).[35]


B) Yuchen Fan & Qiang Zhang, CC-BY

Liposomes are spherical shape, phospholipid vesicles that can be formed with one or more lipid bilayers with phospholipids or cholesterols (Figure 3A).[36] The ability of liposomes to encapsulate both hydrophobic and hydrophilic drug compounds allowed liposomes to be a efficient drug delivery systems (DDS) to deliver a range of drugs in these nano-carriers.[36]

Liposomal formulations of anthracyclines have been developed to maintain or even enhance the therapeutic efficacy of anthracyclines while reduce its limiting toxicities to heathy 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 (Figure 3B).[37][25][38] 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.[39] 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.[29][40] 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.[41]

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 (Table 3).[29] 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.[29] Despite this, the maximum cumulative dose for Doxil is still higher compared to doxorubicin due to its cardioprotective characteristics.[39]

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.[39] Myocet has similar efficacy as conventional doxorubicin, while significantly reducing cardiac toxicity.[42][43][44]

Table 3. Characteristic comparison between Doxil and Myocet
Doxil Myocet References
Composition of liposomes PEG-phospholipid

Phospholipid

Cholesterol

Phospholipid

Cholesterol

[29][45]
Size 80 nm – 100 nm 150 nm - 250 nm [46]
Drug loading method Ammonium salt gradient Citric acid gradient [29][45]
Pharmacokinetics Dose: Single dose at 10 mg/m2 - 20 mg/m2 Peak plasma concentration: 7.4 μM - 15.3 μM^

Elimination half life: 50.2 h - 54.5 h

* using AIDS-related Kaposi's sarcoma patient as example

^ converted into molarity using doxorubicin molecular weight at 543.52 g/mol

Dose: Single dose at 60 mg/m2

Peak plasma concentration: 16 μM

Elimination half life: 16.4 h

* using metastatic breast cancer patient as example (in combination with cyclophosphamide)

[29][47]
Clinical indication AIDS-related Kaposi's sarcoma, recurrent ovarian cancer and metastatic breast cancer Metastatic breast cancer [25]

Clinical trials

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. Table 4 describes some of the successful candidates that are being explored in clinical trials.

Table 4. Nanotechnology-based anthracycline formulations in various clinical stages
Name System Composition Indication Status/Clinical Trial ID Company References
Livatag® Nanoparticles Polyisohexylcyanoacrylate (PIHCA) encapsulated doxorubicin Advanced hepatocellular carcinoma after intolerance to Sorafenib Phase III -ongoing

NCT01655693

Onxeo S.A. [25]
ThermoDox® Heat-activated liposomes Doxorubicin encapsulated with lyso-thermosensitive liposomes made from 3 of the following synthetic phospholipids:
  • 1,2-Dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC)
  • 1-stearoyl-2-hydroxy-sn-glycero-3-phosphatidylcholine (MSPC),
  • 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxypoly-ethyleneglycol 2000 (DSPE-MPEG 2000)
 Hepatocellular carcinoma and metastatic liver cancer Phase III - ongoing

NCT02112656

Celsion Corporation [48]
NC-6300/K-912 pH-responsive polymeric micelle Epirubicin encapsulated in acid-labile hydrazone bound PEG polyaspartate block copolymer Advanced solid tumours

Advanced or metastatic soft tissue sarcoma

Phase Ib/II - ongoing

NCT03168061

NanoCarrier Co. Ltd. [49][50]

Adverse drug interactions

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.[51] As they act as antibiotics anthracyclines can reduce the effectiveness of live culture treatments such as Bacillus Calmette-Guerin therapy for bladder cancer.[52] As they act as myelosuppressors anthracyclines can reduce the effectiveness of vaccines by inhibiting the immune system.[53]

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.[54] Trastuzumab (a HER2 antibody used to treat breast cancer) may enhance the cardiotoxicity of anthracyclines[55][56] although the interaction can be minimised by implementing a time interval between anthracycline and trastuzumab administration.[57] Taxanes (except docetaxel) may decrease anthracycline metabolism, increasing serum concentrations of anthracyclines.[58] The recommendation is to treat with anthracyclines first if combination treatment with taxanes is required.[52]

Additional information

Competing interests

The authors declare they have no competing interest.

References

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  14. ↑ 14.0 14.1 McGowan, John V; Chung, Robin; Maulik, Angshuman; Piotrowska, Izabela; Walker, J Malcolm; Yellon, Derek M (2017). "Anthracycline Chemotherapy and Cardiotoxicity". Cardiovascular Drugs and Therapy 31 (1): 63–75. doi:10.1007/s10557-016-6711-0. ISSN 0920-3206. PMID 28185035. PMC PMC5346598. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346598/. 
  15. ↑ 15.0 15.1 Wahba, Hanan Ahmed; El-Hadaad, Hend Ahmed (June 2015). "Current approaches in treatment of triple-negative breast cancer". Cancer Biology & Medicine 12 (2): 106–116. doi:10.7497/j.issn.2095-3941.2015.0030. ISSN 2095-3941. PMID 26175926. PMC PMC4493381. https://www.ncbi.nlm.nih.gov/pubmed/26175926. 
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  18. ↑ Binaschi, M.; Bigioni, M.; Cipollone, A.; Rossi, C.; Goso, C.; Maggi, C. A.; Capranico, G.; Animati, F. (August 2001). "Anthracyclines: selected new developments". Current Medicinal Chemistry. Anti-Cancer Agents 1 (2): 113–130. doi:10.2174/1568011013354723. ISSN 1568-0118. PMID 12678762. https://www.ncbi.nlm.nih.gov/pubmed/12678762. 
  19. ↑ 19.0 19.1 Minotti, Giorgio; Menna, Pierantonio; Salvatorelli, Emanuela; Cairo, Gaetano; Gianni, Luca (June 2004). "Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity". Pharmacological Reviews 56 (2): 185–229. doi:10.1124/pr.56.2.6. ISSN 0031-6997. PMID 15169927. https://www.ncbi.nlm.nih.gov/pubmed/15169927. 
  20. ↑ 20.0 20.1 20.2 Angsutararux, Paweorn; Luanpitpong, Sudjit; Issaragrisil, Surapol (2015). "Chemotherapy-Induced Cardiotoxicity: Overview of the Roles of Oxidative Stress". Oxidative Medicine and Cellular Longevity 2015: 1–13. doi:10.1155/2015/795602. ISSN 1942-0900. https://www.hindawi.com/journals/omcl/2015/795602/. 
  21. ↑ 21.0 21.1 21.2 21.3 21.4 21.5 21.6 21.7 21.8 Simůnek, Tomás; Stérba, Martin; Popelová, Olga; Adamcová, Michaela; Hrdina, Radomír; Gersl, Vladimír (January 2009). "Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron". Pharmacological Reports: PR 61 (1): 154–171. doi:10.1016/S1734-1140(09)70018-0. ISSN 1734-1140. PMID 19307704. https://www.ncbi.nlm.nih.gov/pubmed/19307704. 
  22. ↑ 22.0 22.1 Cutts, Suzanne M.; Rephaeli, Ada; Nudelman, Abraham; Ugarenko, Michal; Phillips, Don R. (2015). "Potential Therapeutic Advantages of Doxorubicin when Activated by Formaldehyde to Function as a DNA Adduct-Forming Agent". Current Topics in Medicinal Chemistry 15 (14): 1409–1422. doi:10.2174/1568026615666150413154512. ISSN 1873-4294. PMID 25866273. https://www.ncbi.nlm.nih.gov/pubmed/25866273. 
  23. ↑ Cutts, Suzanne M.; Nudelman, Abraham; Rephaeli, Ada; Phillips, Don R. (February 2005). "The power and potential of doxorubicin-DNA adducts". IUBMB life 57 (2): 73–81. doi:10.1080/15216540500079093. ISSN 1521-6543. PMID 16036566. https://www.ncbi.nlm.nih.gov/pubmed/16036566. 
  24. ↑ 24.0 24.1 Bartlett, John M. S.; McConkey, Christopher C.; Munro, Alison F.; Desmedt, Christine; Dunn, Janet A.; Larsimont, Denis P.; O'Malley, Frances P.; Cameron, David A. et al. (2015-05-20). "Predicting Anthracycline Benefit: TOP2A and CEP17-Not Only but Also". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 33 (15): 1680–1687. doi:10.1200/JCO.2013.54.7869. ISSN 1527-7755. PMID 25897160. https://www.ncbi.nlm.nih.gov/pubmed/25897160. 
  25. ↑ 25.0 25.1 25.2 25.3 Cagel, Maximiliano; Grotz, Estefanía; Bernabeu, Ezequiel; Moretton, Marcela A.; Chiappetta, Diego A. (02 2017). "Doxorubicin: nanotechnological overviews from bench to bedside". Drug Discovery Today 22 (2): 270–281. doi:10.1016/j.drudis.2016.11.005. ISSN 1878-5832. PMID 27890669. https://www.ncbi.nlm.nih.gov/pubmed/27890669. 
  26. ↑ Scully, Rebecca E.; Lipshultz, Steven E. (2007). "Anthracycline cardiotoxicity in long-term survivors of childhood cancer". Cardiovascular Toxicology 7 (2): 122–128. doi:10.1007/s12012-007-0006-4. ISSN 1530-7905. PMID 17652816. https://www.ncbi.nlm.nih.gov/pubmed/17652816. 
  27. ↑ 27.0 27.1 27.2 27.3 27.4 27.5 27.6 27.7 Ewer, Michael S.; Ewer, Steven M. (September 2015). "Cardiotoxicity of anticancer treatments". Nature Reviews. Cardiology 12 (9): 547–558. doi:10.1038/nrcardio.2015.65. ISSN 1759-5010. PMID 25962976. https://www.ncbi.nlm.nih.gov/pubmed/25962976. 
  28. ↑ Vejpongsa, P.; Yeh, E. T. H. (January 2014). "Topoisomerase 2β: a promising molecular target for primary prevention of anthracycline-induced cardiotoxicity". Clinical Pharmacology and Therapeutics 95 (1): 45–52. doi:10.1038/clpt.2013.201. ISSN 1532-6535. PMID 24091715. https://www.ncbi.nlm.nih.gov/pubmed/24091715. 
  29. ↑ 29.0 29.1 29.2 29.3 29.4 29.5 29.6 29.7 Gabizon, Alberto; Shmeeda, Hilary; Barenholz, Yechezkel (2003). "Pharmacokinetics of pegylated liposomal Doxorubicin: review of animal and human studies". Clinical Pharmacokinetics 42 (5): 419–436. doi:10.2165/00003088-200342050-00002. ISSN 0312-5963. PMID 12739982. https://www.ncbi.nlm.nih.gov/pubmed/12739982. 
  30. ↑ 30.0 30.1 30.2 Jordan, Karin; Behlendorf, Timo; Mueller, Franziska; Schmoll, Hans-Joachim (2009). "Anthracycline extravasation injuries: management with dexrazoxane". Therapeutics and Clinical Risk Management 5: 361–366. doi:10.2147/TCRM.S3694. ISSN 1176-6336. PMID 19536310. PMC PMC2697522. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2697522/. 
  31. ↑ Chou, Hunghsueh; Lin, Hao; Liu, Jacqueline M (2015-07-13). "A tale of the two PEGylated liposomal doxorubicins". OncoTargets and therapy 8: 1719–1720. doi:10.2147/OTT.S79089. ISSN 1178-6930. PMID 26203262. PMC PMC4508070. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508070/. 
  32. ↑ Araujo, F. I.; Proença, F. P. P.; Ferreira, C. G.; Ventilari, S. C.; Rosado de Castro, P. H.; Moreira, R. D.; Fonseca, L. M. B.; Souza, S. a. L. et al. (2015-8). "Use of (99m)Tc-doxorubicin scintigraphy in females with breast cancer: a pilot study". The British Journal of Radiology 88 (1052): 20150268. doi:10.1259/bjr.20150268. ISSN 1748-880X. PMID 26111270. PMC PMC4651371. https://www.ncbi.nlm.nih.gov/pubmed/26111270. 
  33. ↑ 33.0 33.1 Perez, Edith A. (March 2009). "Impact, mechanisms, and novel chemotherapy strategies for overcoming resistance to anthracyclines and taxanes in metastatic breast cancer". Breast Cancer Research and Treatment 114 (2): 195–201. doi:10.1007/s10549-008-0005-6. ISSN 1573-7217. PMID 18443902. https://www.ncbi.nlm.nih.gov/pubmed/18443902. 
  34. ↑ 34.0 34.1 Arnason, Terra; Harkness, Troy (2015-10-16). "Development, Maintenance, and Reversal of Multiple Drug Resistance: At the Crossroads of TFPI1, ABC Transporters, and HIF1α". Cancers 7 (4): 2063–2082. doi:10.3390/cancers7040877. ISSN 2072-6694. PMID 26501324. PMC PMC4695877. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695877/. 
  35. ↑ Fan, Yuchen; Zhang, Qiang (2013-04-01). "Development of liposomal formulations: From concept to clinical investigations". Asian Journal of Pharmaceutical Sciences 8 (2): 81–87. doi:10.1016/j.ajps.2013.07.010. ISSN 1818-0876. https://www.sciencedirect.com/science/article/pii/S1818087613000111. 
  36. ↑ 36.0 36.1 Sercombe, Lisa; Veerati, Tejaswi; Moheimani, Fatemeh; Wu, Sherry Y.; Sood, Anil K.; Hua, Susan (2015-12-01). "Advances and Challenges of Liposome Assisted Drug Delivery". Frontiers in Pharmacology 6. doi:10.3389/fphar.2015.00286. ISSN 1663-9812. PMID 26648870. PMC PMC4664963. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4664963/. 
  37. ↑ Barenholz, Yechezkel (2012-06-10). "Doxil®--the first FDA-approved nano-drug: lessons learned". Journal of Controlled Release: Official Journal of the Controlled Release Society 160 (2): 117–134. doi:10.1016/j.jconrel.2012.03.020. ISSN 1873-4995. PMID 22484195. https://www.ncbi.nlm.nih.gov/pubmed/22484195. 
  38. ↑ Udhrain, Ashish; Skubitz, Keith M.; Northfelt, Donald W. (2007). "Pegylated liposomal doxorubicin in the treatment of AIDS-related Kaposi's sarcoma". International Journal of Nanomedicine 2 (3): 345–352. ISSN 1176-9114. PMID 18019833. PMC PMC2676669. https://www.ncbi.nlm.nih.gov/pubmed/18019833. 
  39. ↑ 39.0 39.1 39.2 Soloman, Rebecca; Gabizon, Alberto A. (February 2008). "Clinical pharmacology of liposomal anthracyclines: focus on pegylated liposomal Doxorubicin". Clinical Lymphoma & Myeloma 8 (1): 21–32. doi:10.3816/CLM.2008.n.001. ISSN 1557-9190. PMID 18501085. https://www.ncbi.nlm.nih.gov/pubmed/18501085. 
  40. ↑ Haran, G.; Cohen, R.; Bar, L. K.; Barenholz, Y. (1993-09-19). "Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases". Biochimica Et Biophysica Acta 1151 (2): 201–215. doi:10.1016/0005-2736(93)90105-9. ISSN 0006-3002. PMID 8373796. https://www.ncbi.nlm.nih.gov/pubmed/8373796. 
  41. ↑ Maeda, Hiroshi; Nakamura, Hideaki; Fang, Jun (2013-1). "The EPR effect for macromolecular drug delivery to solid tumors: Improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo". Advanced Drug Delivery Reviews 65 (1): 71–79. doi:10.1016/j.addr.2012.10.002. ISSN 1872-8294. PMID 23088862. https://www.ncbi.nlm.nih.gov/pubmed/23088862. 
  42. ↑ Batist, Gerald (2007). "Cardiac safety of liposomal anthracyclines". Cardiovascular Toxicology 7 (2): 72–74. doi:10.1007/s12012-007-0014-4. ISSN 1530-7905. PMID 17652807. https://www.ncbi.nlm.nih.gov/pubmed/17652807. 
  43. ↑ Batist, Gerald; Barton, Jeremy; Chaikin, Philip; Swenson, Christine; Welles, Lauri (December 2002). "Myocet (liposome-encapsulated doxorubicin citrate): a new approach in breast cancer therapy". Expert Opinion on Pharmacotherapy 3 (12): 1739–1751. doi:10.1517/14656566.3.12.1739. ISSN 1465-6566. PMID 12472371. https://www.ncbi.nlm.nih.gov/pubmed/12472371. 
  44. ↑ Leonard, R. C. F.; Williams, S.; Tulpule, A.; Levine, A. M.; Oliveros, S. (August 2009). "Improving the therapeutic index of anthracycline chemotherapy: focus on liposomal doxorubicin (Myocet)". Breast (Edinburgh, Scotland) 18 (4): 218–224. doi:10.1016/j.breast.2009.05.004. ISSN 1532-3080. PMID 19656681. https://www.ncbi.nlm.nih.gov/pubmed/19656681. 
  45. ↑ 45.0 45.1 Swenson, CE; Perkins, WR; Roberts, P; Janoff AS (2005) "Liposome technology and the development of Myocet™ (liposomal doxorubicin citrate)". The Breast 10: 1–7. 2001-06-01. doi:10.1016/S0960-9776(01)80001-1. ISSN 0960-9776. https://www.sciencedirect.com/science/article/pii/S0960977601800011. 
  46. ↑ Bulbake, Upendra; Doppalapudi, Sindhu; Kommineni, Nagavendra; Khan, Wahid (2017-03-27). "Liposomal Formulations in Clinical Use: An Updated Review". Pharmaceutics 9 (2). doi:10.3390/pharmaceutics9020012. ISSN 1999-4923. PMID 28346375. PMC PMC5489929. https://www.ncbi.nlm.nih.gov/pubmed/28346375. 
  47. ↑ Mross, Klaus; Niemann, Bernward; Massing, Ulrich; Drevs, Joachim; Unger, Clemens; Bhamra, Rupinder; Swenson, Christine E. (2004-08-21). "Pharmacokinetics of liposomal doxorubicin (TLC-D99; Myocet) in patients with solid tumors: an open-label, single-dose study". Cancer Chemotherapy and Pharmacology 54 (6): 514–524. doi:10.1007/s00280-004-0825-y. ISSN 0344-5704. https://link.springer.com/article/10.1007/s00280-004-0825-y. 
  48. ↑ Poon, Ronnie T. P.; Borys, Nicholas (February 2009). "Lyso-thermosensitive liposomal doxorubicin: a novel approach to enhance efficacy of thermal ablation of liver cancer". Expert Opinion on Pharmacotherapy 10 (2): 333–343. doi:10.1517/14656560802677874. ISSN 1744-7666. PMID 19236203. https://www.ncbi.nlm.nih.gov/pubmed/19236203. 
  49. ↑ Mukai, Hirofumi; Kogawa, Takahiro; Matsubara, Nobuaki; Naito, Yoichi; Sasaki, Masaoki; Hosono, Ako (06 2017). "A first-in-human Phase 1 study of epirubicin-conjugated polymer micelles (K-912/NC-6300) in patients with advanced or recurrent solid tumors". Investigational New Drugs 35 (3): 307–314. doi:10.1007/s10637-016-0422-z. ISSN 1573-0646. PMID 28054329. https://www.ncbi.nlm.nih.gov/pubmed/28054329. 
  50. ↑ Nishiyama, Nobuhiro; Matsumura, Yasuhiro; Kataoka, Kazunori (July 2016). "Development of polymeric micelles for targeting intractable cancers". Cancer Science 107 (7): 867–874. doi:10.1111/cas.12960. ISSN 1349-7006. PMID 27116635. PMC PMC4946707. https://www.ncbi.nlm.nih.gov/pubmed/27116635. 
  51. ↑ Kivistö, K T; Kroemer, H K; Eichelbaum, M (December 1995). "The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug interactions.". British Journal of Clinical Pharmacology 40 (6): 523–530. doi:10.1111/j.1365-2125.1995.tb05796.x. ISSN 0306-5251. PMID 8703657. PMC PMC1365206. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1365206/. 
  52. ↑ 52.0 52.1 Bedford Laboratories (2012). Product Information: Adriamcycin (Doxorubcin HCl) for Injection, USP. In (pp. 8). Ohio (https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/062921s022lbl.pdf)
  53. ↑ Tacar, Oktay; Sriamornsak, Pornsak; Dass, Crispin R. (February 2013). "Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems". The Journal of Pharmacy and Pharmacology 65 (2): 157–170. doi:10.1111/j.2042-7158.2012.01567.x. ISSN 2042-7158. PMID 23278683. https://www.ncbi.nlm.nih.gov/pubmed/23278683. 
  54. ↑ Lyu, Yi Lisa; Kerrigan, John E.; Lin, Chao-Po; Azarova, Anna M.; Tsai, Yuan-Chin; Ban, Yi; Liu, Leroy F. (2007-09-15). "Topoisomerase IIbeta mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane". Cancer Research 67 (18): 8839–8846. doi:10.1158/0008-5472.CAN-07-1649. ISSN 0008-5472. PMID 17875725. https://www.ncbi.nlm.nih.gov/pubmed/17875725. 
  55. ↑ Ewer, Michael S.; Ewer, Steven M. (2010-09-01). "Troponin I provides insight into cardiotoxicity and the anthracycline-trastuzumab interaction". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 28 (25): 3901–3904. doi:10.1200/JCO.2010.30.6274. ISSN 1527-7755. PMID 20679626. https://www.ncbi.nlm.nih.gov/pubmed/20679626. 
  56. ↑ Rayson, D.; Richel, D.; Chia, S.; Jackisch, C.; van der Vegt, S.; Suter, T. (September 2008). "Anthracycline-trastuzumab regimens for HER2/neu-overexpressing breast cancer: current experience and future strategies". Annals of Oncology: Official Journal of the European Society for Medical Oncology 19 (9): 1530–1539. doi:10.1093/annonc/mdn292. ISSN 1569-8041. PMID 18480068. https://www.ncbi.nlm.nih.gov/pubmed/18480068. 
  57. ↑ Slamon, D. J.; Leyland-Jones, B.; Shak, S.; Fuchs, H.; Paton, V.; Bajamonde, A.; Fleming, T.; Eiermann, W. et al. (2001-03-15). "Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2". The New England Journal of Medicine 344 (11): 783–792. doi:10.1056/NEJM200103153441101. ISSN 0028-4793. PMID 11248153. https://www.ncbi.nlm.nih.gov/pubmed/11248153. 
  58. ↑ Gianni, L.; Viganò, L.; Locatelli, A.; Capri, G.; Giani, A.; Tarenzi, E.; Bonadonna, G. (May 1997). "Human pharmacokinetic characterization and in vitro study of the interaction between doxorubicin and paclitaxel in patients with breast cancer". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 15 (5): 1906–1915. doi:10.1200/JCO.1997.15.5.1906. ISSN 0732-183X. PMID 9164201. https://www.ncbi.nlm.nih.gov/pubmed/9164201. 
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