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ction 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 m 2 550 mg m 2 and 700 mg m 2 4 therefore the lifetime cumulative doxorubicin exposure is limited to 400 450 mg m 2 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 troponin level immediately after administration 35 biopsy also allows early detection of cardiac injury by evaluating heart ultrastructure changes 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 advances in developing more sensitive imaging techniques and biomarkers allow early detection of cardiotoxicity and allow cardioprotective intervention to prevent anthracycline mediated cardiotoxicity 35 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 liposomal formulations of anthracyclines discussed below have been developed and used to reduce cardiac damage 37 other novel anthracycline analogues such as epirubicin and idarubicin also provide options to reduce adverse cardiac events these analogues have failed to show superior anti cancer activity to the parent compounds 6 35 an alternative drug administration method involving continuous infusion for 72 h as compared to bolus administration provides some protection and can be used when high cumulative doses are anticipated 35 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 m 2 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 99m tc 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 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 42 resistance to anthracyclines involves many factors but it is often related to overexpression of the transmembrane drug efflux protein p glycoprotein p gp or multidrug resistance protein 1 mrp1 which removes anthracyclines from cancer cells 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 43 liposomal based clinical formulations edit schematic representation of pegylated liposomal doxorubicin cryo tem images of doxil pegylated liposomal doxorubicin 44 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 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 46 21 47 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 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 37 49 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 50 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 37 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 m 2 every 4 weeks compared to free doxorubicin at 60 mg m 2 every 3 weeks 37 despite this the maximum cumulative dose for doxil is still higher compared to doxorubicin due to its cardioprotective characteristics 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 doxorubicin is loaded into the liposomes just before administration to patients with a maximum single dose of 75 mg m 2 every 3 weeks 48 myocet has similar efficacy as conventional doxorubicin while significantly reducing cardiac toxicity 51 52 53 characteristic comparison between doxil and myocet 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 m 2 20 mg m 2 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 m 2 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 edit 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 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 as they act as myelosuppressors anthracyclines can reduce the effectiveness of vaccines by inhibiting the immune system 59 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 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