Anthracycline
The first anthracycline discovered was daunorubicin (trade name Daunomycin), which is produced naturally by Streptomyces peucetius, a species of Actinomycetota.
The basic structure of anthracyclines is that of a tetracyclic molecule with an anthraquinone backbone connected to a sugar moiety by a glycosidic linkage.
This modification greatly changes the activity of the drug making it highly effective against a wide range of solid tumours, leukaemia and lymphomas.
[11][12][13][14][15] The first anthracyclines were so successful that thousands of analogues have been produced in attempts to find compounds with improved therapeutic applications.
[5][17] 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.
[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.
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.
[26] 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.
[6] 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.
[28][29] The excessive ROS that cannot be detoxified results in oxidative stress, DNA damage, and lipid peroxidation thereby triggering apoptosis.
[28][29] 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][31] 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.
[33] 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.
In the clinic, a maximum recommended cumulative dose is set for anthracyclines to prevent the development of congestive heart failure.
[35] Cardiac injury that occurs in response to initial doses of anthracycline can be detected by a rise in troponin level immediately after administration.
[35] 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.
[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] A more recent explanation has emerged, in which anthracycline-mediated cardiotoxicity is due to anthracycline-topoisomerase IIb poisoning, leading to downstream oxidative stress.
[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.
[43][42] 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.
[48] 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.
[48] 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.
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.
[57] As they act as antibiotics anthracyclines can reduce the effectiveness of live culture treatments such as Bacillus Calmette-Guerin therapy for bladder cancer.
[58] This article was adapted from the following source under a CC BY 4.0 license (2019) (reviewer reports): Alison Cheong; Sean McGrath; Suzanne Cutts (6 December 2018).
