Anthracycline
Anthracyclines are a class of drugs used in cancer chemotherapy that are extracted from Streptomyces bacterium.[2][3] These compounds are used to treat many cancers, including leukemias, lymphomas, breast, stomach, uterine, ovarian, bladder cancer, and lung cancers. The first anthracycline discovered was daunorubicin (trade name Daunomycin), which is produced naturally by Streptomyces peucetius, a species of Actinomycetota. Clinically the most important anthracyclines are doxorubicin, daunorubicin, epirubicin and idarubicin.[4]
The anthracyclines are among the most effective anticancer treatments ever developed and are effective against more types of cancer than any other class of chemotherapeutic agents.[4][5][6] Their main adverse effect is cardiotoxicity, which considerably limits their usefulness. Use of anthracyclines has also been shown to be significantly associated with cycle 1 severe or febrile neutropenia.[7] Other adverse effects include vomiting.
The drugs act mainly by
History
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.[10][11][12][13][14]
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.[15] Idarubicin is a fat soluble variant of daunorubicin and is orally bioavailable.[4][16]
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.[17] Disaccharide analogues have been shown to retain anticancer activity, and are being further investigated with respect to their mechanism of action.[18]
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.[19] 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.[20] 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.[20]
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.[21][22][23][24]
Mechanism of action
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,[26] 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. The chromophore moiety of anthracyclines has intercalating function and inserts in between the adjacent base pair of DNA.[26] The intercalating function inhibits DNA and RNA synthesis in highly replicating cells, subsequently blocking the transcription and replication processes.[26]
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.
Reactive oxygen species
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.[28][29] In addition, the availability of cellular iron catalyses redox reactions and further generates ROS.[28][29] The excessive ROS that cannot be detoxified results in oxidative stress, DNA damage, and lipid peroxidation thereby triggering apoptosis.[28][29]
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.[30] 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.[30][31]
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.[32] 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.[32]
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
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.
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 anthracycline treatment | Dilated cardiomyopathy, restrictive cardiomyopathy (uncommon), left ventricular contractile dysfunction, congestive heart failure |
Delayed/late onset chronic | More than 1 year after completing anthracycline 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.[35] 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.[19] 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.[35] 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.[29] Children are particularly at risk due to the anthracycline activity that can compromise the development of the immature heart.[35]
Cardiac injury that occurs in response to initial doses of anthracycline can be detected by a rise in
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.[29] 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.[29]
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.[29] A more recent explanation has emerged, in which anthracycline-mediated cardiotoxicity is due to anthracycline-topoisomerase IIb poisoning, leading to downstream oxidative stress.[36]
In order to reduce the impact of cardiac injury in response to anthracyclines, a few cardioprotective strategies have been explored.
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%.[38] Extravasation causes serious complications to surrounding tissues with the symptoms of tissue necrosis and skin ulceration.[38] 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.[38] 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.[39][37]
There is no high quality evidence to confirm if cardioprotective treatments are effective.[40] 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.[41]
In some cases, anthracyclines may be ineffective due to the development of
Liposomal-based clinical formulations
Liposomes are spherical shape, phospholipid vesicles that can be formed with one or more lipid bilayers with phospholipids or cholesterols.[45] 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.[45]
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
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.
Doxil | Myocet | References | |
---|---|---|---|
Composition of liposomes | PEG-phospholipid
Phospholipid Cholesterol |
Phospholipid
Cholesterol |
[37][54] |
Size | 80 nm – 100 nm | 150 nm - 250 nm | [55] |
Drug loading method | Ammonium salt gradient | Citric acid gradient | [37][54] |
Pharmacokinetics | Dose: Single dose at 10 mg/m2 - 20 mg/m2 Peak plasma concentration: 7.4 μM – 15.3 μM[a]
Elimination half life: 50.2 h – 54.5 h[b] |
Dose: Single dose at 60 mg/m2
Peak plasma concentration: 16 μM Elimination half life: 16.4 h[c] |
[37][56] |
Clinical indication | AIDS-related Kaposi's sarcoma, recurrent ovarian cancer and metastatic breast cancer | Metastatic breast cancer | [21] |
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
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.[60] Trastuzumab (a HER2 antibody used to treat breast cancer) may enhance the cardiotoxicity of anthracyclines[61][62] although the interaction can be minimised by implementing a time interval between anthracycline and trastuzumab administration.[63] Taxanes (except docetaxel) may decrease anthracycline metabolism, increasing serum concentrations of anthracyclines.[64] The recommendation is to treat with anthracyclines first if combination treatment with taxanes is required.[58]
See also
References
This article was adapted from the following source under a CC BY 4.0 license (2019) (reviewer reports):
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Notes
External links
- Media related to Anthracyclines at Wikimedia Commons