- 原作者信息：Alison Cheong1*, Sean McGrath1*, Suzanne Cutts2
- 1：拉筹伯大学 澳大利亚墨尔本
- 2：拉筹伯大学 澳大利亚墨尔本；通讯作者，邮箱：firstname.lastname@example.org
摘要：蒽环类药物是一类在临床上具有重要意义的抗肿瘤化疗药物，能治疗多种实体瘤以及血液瘤。头两种获得报导的蒽环类药物是蒽环霉素和柔红霉素，它们是从波赛链霉菌（Streptomyces peucetius）的菌株中分离得到的。目前，临床上最常用的蒽环类药物包括多柔比星和柔红霉素，以及这两种药物的半合成衍生物表柔比星和伊达比星。蒽环类药物能抑制拓扑异构酶II的活性，并插入DNA分子中，使DNA分子断裂、DNA合成停止。蒽环类药物最严重的副作用是剂量依赖的累积性心脏毒性。为避免出现这样的副作用，需要调整给药量，使血药浓度峰值控制在400-450 mg/m2。一部分蒽环类药物使用脂质体制剂，能增加药物的半衰期，使药物浓度能在更长时间里维持在治疗浓度之上、血浆中自由的药物分子浓度减少。一些蒽环类药物的纳米颗粒制剂已进入临床实验阶段。
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.
Figure 1 | Doxorubicin as an intercalating agent. Two doxorubicin molecules intercalated within DNA.
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. About the same time Dubost and coworkers in France also discovered the compound and named it rubidomycin. 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 (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.
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. Idarubicin is a fat soluble variant of daunorubicin and is orally bioavailable.
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. Disaccharide analogues have been shown to retain anticancer activity, and are being further investigated with respect to their mechanism of action.
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. 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. 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.
|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|
|Breast, ovarian, gastric, lung cancers, and lymphomas|
|Acute myeloid leukemia (AML)|
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). 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. 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 (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. 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. 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.
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. 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.
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).
|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. 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-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.
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. 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 where anthracycline-mediated cardiotoxicity is due to anthracycline-topoisomerase IIb poisoning, leading to downstream oxidative stress.
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. 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. 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.
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%. 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 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 patients who are anticipated to have a beneficial effect from high cumulative doses of doxorubicin.
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.
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). 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. 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.
Liposomes are spherical shape, phospholipid vesicles that can be formed with one or more lipid bilayers with phospholipids or cholesterols (Figure 3A). 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.
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). 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. 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. 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.
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). 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.
|Composition of liposomes||PEG-phospholipid
|Size||80 nm – 100 nm||150 nm - 250 nm|||
|Drug loading method||Ammonium salt gradient||Citric acid gradient|||
|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)
|Clinical indication||AIDS-related Kaposi's sarcoma, recurrent ovarian cancer and metastatic breast cancer||Metastatic breast cancer|||
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.
|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||Onxeo S.A.|||
|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||Celsion Corporation|||
|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||NanoCarrier Co. Ltd.|||
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. As they act as antibiotics anthracyclines can reduce the effectiveness of live culture treatments such as Bacillus Calmette-Guerin therapy for bladder cancer. As they act as myelosuppressors anthracyclines can reduce the effectiveness of vaccines by inhibiting the immune system.
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. Trastuzumab (a HER2 antibody used to treat breast cancer) may enhance the cardiotoxicity of anthracyclines although the interaction can be minimised by implementing a time interval between anthracycline and trastuzumab administration. Taxanes (except docetaxel) may decrease anthracycline metabolism, increasing serum concentrations of anthracyclines. The recommendation is to treat with anthracyclines first if combination treatment with taxanes is required.
The authors declare they have no competing interest.
- Dubost, M.; Ganter, P.; Maral, R.; Ninet, L.; Pinnert, S.; Preudhomme, J.; Werner, G. H. RUBIDOMYCIN: A NEW ANTIBIOTIC WITH CYTOSTATIC PROPERTIES. Cancer Chemotherapy Reports. September 1964, 41: 35–36. ISSN 0069-0112. PMID 14213139.
- Frederick, C. A.; Williams, L. D.; Ughetto, G.; van der Marel, G. A.; van Boom, J. H.; Rich, A.; Wang, A. H. Structural comparison of anticancer drug-DNA complexes: adriamycin and daunomycin. Biochemistry. 1990-03-13, 29 (10): 2538–2549. ISSN 0006-2960. PMID 2334681.
- DI MARCO, A.; GAETANI, M.; OREZZI, P.; SCARPINATO, B. M.; SILVESTRINI, R.; SOLDATI, M.; DASDIA, T.; VALENTINI, L. ‘Daunomycin’, a New Antibiotic of the Rhodomycin Group. Nature. 1964/02, 201 (4920): 706–707. ISSN 1476-4687. doi:10.1038/201706a0 （英语）.
- Weiss, R. B. The anthracyclines: will we ever find a better doxorubicin?. Seminars in Oncology. December 1992, 19 (6): 670–686. ISSN 0093-7754. PMID 1462166.
- Arcamone, F.; Cassinelli, G.; Fantini, G.; Grein, A.; Orezzi, P.; Pol, C.; Spalla, C. Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. caesius. Biotechnology and Bioengineering. November 1969, 11 (6): 1101–1110. ISSN 0006-3592. PMID 5365804. doi:10.1002/bit.260110607.
- Blum, R. H.; Carter, S. K. Adriamycin. A new anticancer drug with significant clinical activity. Annals of Internal Medicine. February 1974, 80 (2): 249–259. ISSN 0003-4819. PMID 4590654.
- Cancer management in man : chemotherapy, biological therapy, hyperthermia and supporting measures. Minev, Boris R. Dordrecht: Springer. 2011. ISBN 9789048197040. OCLC 704395391.
- DeVita, Hellman, and Rosenberg's cancer : principles & practice of oncology. DeVita, Vincent T., Jr., 1935-, Lawrence, Theodore S., Rosenberg, Steven A. 8th ed. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins. 2008. ISBN 9780781772075. OCLC 192027662.
- Takemura, Genzou; Fujiwara, Hisayoshi. Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management. Progress in Cardiovascular Diseases. March 2007, 49 (5): 330–352. ISSN 0033-0620. PMID 17329180. doi:10.1016/j.pcad.2006.10.002.
- Arcamone, Federico & Penco, S & Vigevani, A. (1975). Adriamycin (NSC 123127): new chemical developments and analogs. CANCER CHEMOTHER.REP.. 6. 123-129.
- Arcamone, F.; Bernardi, L.; Giardino, P.; Patelli, B.; Marco, A.; Casazza, A. M.; Pratesi, G.; Reggiani, P. Synthesis and antitumor activity of 4-demethoxydaunorubicin, 4-demethoxy-7,9-diepidaunorubicin, and their beta anomers. Cancer Treatment Reports. July 1976, 60 (7): 829–834. ISSN 0361-5960. PMID 1009518.
- Evison, Benny J.; Sleebs, Brad E.; Watson, Keith G.; Phillips, Don R.; Cutts, Suzanne M. Mitoxantrone, More than Just Another Topoisomerase II Poison. Medicinal Research Reviews. 2016-3, 36 (2): 248–299. ISSN 1098-1128. PMID 26286294. doi:10.1002/med.21364.
- Marinello, Jessica; Delcuratolo, Maria; Capranico, Giovanni. Anthracyclines as Topoisomerase II Poisons: From Early Studies to New Perspectives. International Journal of Molecular Sciences. 2018-11-06, 19 (11). ISSN 1422-0067. PMID 30404148. doi:10.3390/ijms19113480.
- McGowan, John V; Chung, Robin; Maulik, Angshuman; Piotrowska, Izabela; Walker, J Malcolm; Yellon, Derek M. Anthracycline Chemotherapy and Cardiotoxicity. Cardiovascular Drugs and Therapy. 2017, 31 (1): 63–75. ISSN 0920-3206. PMC 5346598. PMID 28185035. doi:10.1007/s10557-016-6711-0.
- Wahba, Hanan Ahmed; El-Hadaad, Hend Ahmed. Current approaches in treatment of triple-negative breast cancer. Cancer Biology & Medicine. June 2015, 12 (2): 106–116. ISSN 2095-3941. PMC 4493381. PMID 26175926. doi:10.7497/j.issn.2095-3941.2015.0030.
- Guo, Baoqing; Tam, Adam; Santi, Stacey A.; Parissenti, Amadeo M. Role of autophagy and lysosomal drug sequestration in acquired resistance to doxorubicin in MCF-7 cells. BMC cancer. 2016-09-29, 16 (1): 762. ISSN 1471-2407. PMC 5043608. PMID 27687594. doi:10.1186/s12885-016-2790-3.
- Gewirtz, D. A. A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochemical Pharmacology. 1999-04-01, 57 (7): 727–741. ISSN 0006-2952. PMID 10075079.
- Binaschi, M.; Bigioni, M.; Cipollone, A.; Rossi, C.; Goso, C.; Maggi, C. A.; Capranico, G.; Animati, F. Anthracyclines: selected new developments. Current Medicinal Chemistry. Anti-Cancer Agents. August 2001, 1 (2): 113–130. ISSN 1568-0118. PMID 12678762.
- Minotti, Giorgio; Menna, Pierantonio; Salvatorelli, Emanuela; Cairo, Gaetano; Gianni, Luca. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacological Reviews. June 2004, 56 (2): 185–229. ISSN 0031-6997. PMID 15169927. doi:10.1124/pr.56.2.6.
- Angsutararux, Paweorn; Luanpitpong, Sudjit; Issaragrisil, Surapol. Chemotherapy-Induced Cardiotoxicity: Overview of the Roles of Oxidative Stress. Oxidative Medicine and Cellular Longevity. 2015, 2015: 1–13. ISSN 1942-0900. doi:10.1155/2015/795602 （英语）.
- Simůnek, Tomás; Stérba, Martin; Popelová, Olga; Adamcová, Michaela; Hrdina, Radomír; Gersl, Vladimír. Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacological reports: PR. January 2009, 61 (1): 154–171. ISSN 1734-1140. PMID 19307704.
- Cutts, Suzanne M.; Rephaeli, Ada; Nudelman, Abraham; Ugarenko, Michal; Phillips, Don R. Potential Therapeutic Advantages of Doxorubicin when Activated by Formaldehyde to Function as a DNA Adduct-Forming Agent. Current Topics in Medicinal Chemistry. 2015, 15 (14): 1409–1422. ISSN 1873-4294. PMID 25866273.
- Cutts, Suzanne M.; Nudelman, Abraham; Rephaeli, Ada; Phillips, Don R. The power and potential of doxorubicin-DNA adducts. IUBMB life. February 2005, 57 (2): 73–81. ISSN 1521-6543. PMID 16036566. doi:10.1080/15216540500079093.
- 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.; Earl, Helena M. Predicting Anthracycline Benefit: TOP2A and CEP17-Not Only but Also. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2015-05-20, 33 (15): 1680–1687. ISSN 1527-7755. PMID 25897160. doi:10.1200/JCO.2013.54.7869.
- Cagel, Maximiliano; Grotz, Estefanía; Bernabeu, Ezequiel; Moretton, Marcela A.; Chiappetta, Diego A. Doxorubicin: nanotechnological overviews from bench to bedside. Drug Discovery Today. 02 2017, 22 (2): 270–281. ISSN 1878-5832. PMID 27890669. doi:10.1016/j.drudis.2016.11.005.
- Scully, Rebecca E.; Lipshultz, Steven E. Anthracycline cardiotoxicity in long-term survivors of childhood cancer. Cardiovascular Toxicology. 2007, 7 (2): 122–128. ISSN 1530-7905. PMID 17652816. doi:10.1007/s12012-007-0006-4.
- Ewer, Michael S.; Ewer, Steven M. Cardiotoxicity of anticancer treatments. Nature Reviews. Cardiology. September 2015, 12 (9): 547–558. ISSN 1759-5010. PMID 25962976. doi:10.1038/nrcardio.2015.65.
- Vejpongsa, P.; Yeh, E. T. H. Topoisomerase 2β: a promising molecular target for primary prevention of anthracycline-induced cardiotoxicity. Clinical Pharmacology and Therapeutics. January 2014, 95 (1): 45–52. ISSN 1532-6535. PMID 24091715. doi:10.1038/clpt.2013.201.
- Gabizon, Alberto; Shmeeda, Hilary; Barenholz, Yechezkel. Pharmacokinetics of pegylated liposomal Doxorubicin: review of animal and human studies. Clinical Pharmacokinetics. 2003, 42 (5): 419–436. ISSN 0312-5963. PMID 12739982. doi:10.2165/00003088-200342050-00002.
- Jordan, Karin; Behlendorf, Timo; Mueller, Franziska; Schmoll, Hans-Joachim. Anthracycline extravasation injuries: management with dexrazoxane. Therapeutics and Clinical Risk Management. 2009, 5: 361–366. ISSN 1176-6336. PMC 2697522. PMID 19536310.
- Chou, Hunghsueh; Lin, Hao; Liu, Jacqueline M. A tale of the two PEGylated liposomal doxorubicins. OncoTargets and therapy. 2015-07-13, 8: 1719–1720. ISSN 1178-6930. PMC 4508070. PMID 26203262. doi:10.2147/OTT.S79089.
- 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.; Gutfilen, B. Use of (99m)Tc-doxorubicin scintigraphy in females with breast cancer: a pilot study. The British Journal of Radiology. 2015-8, 88 (1052): 20150268. ISSN 1748-880X. PMC 4651371. PMID 26111270. doi:10.1259/bjr.20150268.
- Perez, Edith A. Impact, mechanisms, and novel chemotherapy strategies for overcoming resistance to anthracyclines and taxanes in metastatic breast cancer. Breast Cancer Research and Treatment. March 2009, 114 (2): 195–201. ISSN 1573-7217. PMID 18443902. doi:10.1007/s10549-008-0005-6.
- Arnason, Terra; Harkness, Troy. Development, Maintenance, and Reversal of Multiple Drug Resistance: At the Crossroads of TFPI1, ABC Transporters, and HIF1α. Cancers. 2015-10-16, 7 (4): 2063–2082. ISSN 2072-6694. PMC 4695877. PMID 26501324. doi:10.3390/cancers7040877.
- Sercombe, Lisa; Veerati, Tejaswi; Moheimani, Fatemeh; Wu, Sherry Y.; Sood, Anil K.; Hua, Susan. Advances and Challenges of Liposome Assisted Drug Delivery. Frontiers in Pharmacology. 2015-12-01, 6. ISSN 1663-9812. PMC 4664963. PMID 26648870. doi:10.3389/fphar.2015.00286.
- Barenholz, Yechezkel. Doxil®--the first FDA-approved nano-drug: lessons learned. Journal of Controlled Release: Official Journal of the Controlled Release Society. 2012-06-10, 160 (2): 117–134. ISSN 1873-4995. PMID 22484195. doi:10.1016/j.jconrel.2012.03.020.
- Udhrain, Ashish; Skubitz, Keith M.; Northfelt, Donald W. Pegylated liposomal doxorubicin in the treatment of AIDS-related Kaposi's sarcoma. International Journal of Nanomedicine. 2007, 2 (3): 345–352. ISSN 1176-9114. PMC 2676669. PMID 18019833.
- Soloman, Rebecca; Gabizon, Alberto A. Clinical pharmacology of liposomal anthracyclines: focus on pegylated liposomal Doxorubicin. Clinical Lymphoma & Myeloma. February 2008, 8 (1): 21–32. ISSN 1557-9190. PMID 18501085.
- Haran, G.; Cohen, R.; Bar, L. K.; Barenholz, Y. Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases. Biochimica Et Biophysica Acta. 1993-09-19, 1151 (2): 201–215. ISSN 0006-3002. PMID 8373796.
- Maeda, Hiroshi; Nakamura, Hideaki; Fang, Jun. 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. 2013-1, 65 (1): 71–79. ISSN 1872-8294. PMID 23088862. doi:10.1016/j.addr.2012.10.002.
- Batist, Gerald. Cardiac safety of liposomal anthracyclines. Cardiovascular Toxicology. 2007, 7 (2): 72–74. ISSN 1530-7905. PMID 17652807. doi:10.1007/s12012-007-0014-4.
- Batist, Gerald; Barton, Jeremy; Chaikin, Philip; Swenson, Christine; Welles, Lauri. Myocet (liposome-encapsulated doxorubicin citrate): a new approach in breast cancer therapy. Expert Opinion on Pharmacotherapy. December 2002, 3 (12): 1739–1751. ISSN 1465-6566. PMID 12472371. doi:10.1517/14656518.104.22.1689.
- Leonard, R. C. F.; Williams, S.; Tulpule, A.; Levine, A. M.; Oliveros, S. Improving the therapeutic index of anthracycline chemotherapy: focus on liposomal doxorubicin (Myocet). Breast (Edinburgh, Scotland). August 2009, 18 (4): 218–224. ISSN 1532-3080. PMID 19656681. doi:10.1016/j.breast.2009.05.004.
- Swenson, CE; Perkins, WR; Roberts, P; Janoff AS (2005) Liposome technology and the development of Myocet™ (liposomal doxorubicin citrate). The Breast. 2001-06-01, 10: 1–7. ISSN 0960-9776. doi:10.1016/S0960-9776(01)80001-1.
- Bulbake, Upendra; Doppalapudi, Sindhu; Kommineni, Nagavendra; Khan, Wahid. Liposomal Formulations in Clinical Use: An Updated Review. Pharmaceutics. 2017-03-27, 9 (2). ISSN 1999-4923. PMC 5489929. PMID 28346375. doi:10.3390/pharmaceutics9020012.
- Mross, Klaus; Niemann, Bernward; Massing, Ulrich; Drevs, Joachim; Unger, Clemens; Bhamra, Rupinder; Swenson, Christine E. Pharmacokinetics of liposomal doxorubicin (TLC-D99; Myocet) in patients with solid tumors: an open-label, single-dose study. Cancer Chemotherapy and Pharmacology. 2004-08-21, 54 (6): 514–524. ISSN 0344-5704. doi:10.1007/s00280-004-0825-y （英语）.
- Poon, Ronnie T. P.; Borys, Nicholas. Lyso-thermosensitive liposomal doxorubicin: a novel approach to enhance efficacy of thermal ablation of liver cancer. Expert Opinion on Pharmacotherapy. February 2009, 10 (2): 333–343. ISSN 1744-7666. PMID 19236203. doi:10.1517/14656560802677874.
- Mukai, Hirofumi; Kogawa, Takahiro; Matsubara, Nobuaki; Naito, Yoichi; Sasaki, Masaoki; Hosono, Ako. 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. 06 2017, 35 (3): 307–314. ISSN 1573-0646. PMID 28054329. doi:10.1007/s10637-016-0422-z.
- Nishiyama, Nobuhiro; Matsumura, Yasuhiro; Kataoka, Kazunori. Development of polymeric micelles for targeting intractable cancers. Cancer Science. July 2016, 107 (7): 867–874. ISSN 1349-7006. PMC 4946707. PMID 27116635. doi:10.1111/cas.12960.
- Kivistö, K T; Kroemer, H K; Eichelbaum, M. The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug interactions.. British Journal of Clinical Pharmacology. December 1995, 40 (6): 523–530. ISSN 0306-5251. PMC 1365206. PMID 8703657.
- 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)
- Tacar, Oktay; Sriamornsak, Pornsak; Dass, Crispin R. Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems. The Journal of Pharmacy and Pharmacology. February 2013, 65 (2): 157–170. ISSN 2042-7158. PMID 23278683. doi:10.1111/j.2042-7158.2012.01567.x.
- Lyu, Yi Lisa; Kerrigan, John E.; Lin, Chao-Po; Azarova, Anna M.; Tsai, Yuan-Chin; Ban, Yi; Liu, Leroy F. Topoisomerase IIbeta mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Research. 2007-09-15, 67 (18): 8839–8846. ISSN 0008-5472. PMID 17875725. doi:10.1158/0008-5472.CAN-07-1649.
- Ewer, Michael S.; Ewer, Steven M. Troponin I provides insight into cardiotoxicity and the anthracycline-trastuzumab interaction. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2010-09-01, 28 (25): 3901–3904. ISSN 1527-7755. PMID 20679626. doi:10.1200/JCO.2010.30.6274.
- Rayson, D.; Richel, D.; Chia, S.; Jackisch, C.; van der Vegt, S.; Suter, T. 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. September 2008, 19 (9): 1530–1539. ISSN 1569-8041. PMID 18480068. doi:10.1093/annonc/mdn292.
- Slamon, D. J.; Leyland-Jones, B.; Shak, S.; Fuchs, H.; Paton, V.; Bajamonde, A.; Fleming, T.; Eiermann, W.; Wolter, J. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. The New England Journal of Medicine. 2001-03-15, 344 (11): 783–792. ISSN 0028-4793. PMID 11248153. doi:10.1056/NEJM200103153441101.
- Gianni, L.; Viganò, L.; Locatelli, A.; Capri, G.; Giani, A.; Tarenzi, E.; Bonadonna, G. 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. May 1997, 15 (5): 1906–1915. ISSN 0732-183X. PMID 9164201. doi:10.1200/JCO.1922.214.171.1246.