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  • br In clinical practice cumulative anthracycline

    2020-08-28


    In clinical practice, cumulative anthracycline doses are associated with the risk of developing heart failure. Accordingly, such cumulative doses are avoided whenever clinically possible. Possibly, peak drug levels and associated toxicity are reduced by prolonged infusion proto-cols, which are particularly used in pediatric oncology [52]. In preclinical experiments, ischemic conditioning protects cardiomyocytes from anthracycline-induced 65162-13-2 death [53], but this strategy remains to be addressed in further translational and clinical studies. r> Doxorubicin, daunorubicin, epirubicin, idarubicin, and mitoxantrone induce heart failure [4]. Heart failure is an independent predictor of mortality in anthracycline recipients, and the majority of patients with established anthracycline-related heart failure die over the following two years. The outcome of established anthracycline-related heart fail-ure is comparable to that of matched cohorts with dilative heart failure [14]. Primary prevention and treatment according to heart failure guidelines are, therefore, recommended. Heart failure goes along with arrhythmias, and vascular side effects can become manifest as hyper-tension and/or thrombosis [1,14,15].
    Anthracyclines and HER2 inhibitors (e.g., the antibody trastuzumab or the small molecule inhibitor lapatinib) are standard of care in systemic treatment of patients with HER2-positive breast cancer in the adjuvant and in the palliative setting, and in palliative therapy of HER2-positive gastric cancer. As HER2 inhibitors per se have cardiotoxic potential [4], the simultaneous application of these agents with anthracyclines is avoided in particular in patients treated in a curative setting. The cellular signaling following combined anthracycline and HER2 inhibition is not fully clear; however, inhibition of the HER2 receptor on cardiomyocytes and the corresponding signal transduction promotes increased ROS for-mation [54]. Consequently, most treatment protocols sequence these agents with e.g. trastuzumab co-administered with taxanes. Also, anthracycline-free protocols have been developed, which are particu-larly appropriate in patients at high risk for cardiotoxicity.
    Alkylating agents (e.g. cyclophosphamide and ifosfamide) have a broad spectrum of indications including lymphomas, leukemia, solid tu-mors and autoimmune disorders. The occurrence of cardiotoxicity is dose-dependent and may develop within 7 to 10 days after the initial administration in high dose regimens [55]. Cyclophosphamide induces vascular injury; lipid peroxidation and mitochondrial dysfunction have been related to ROS formation and DNA damage [56].
    Fluoropyrimidines, such as 5-fluorouracil, are widely used in treat-ment of solid tumors. These drugs may induce acute chest pain as a
    Fig. 1. Molecular/cellular targets of cancer therapy in cardiomyocytes. Classical chemotherapy with anthracyclines has multiple cellular and subcellular targets in the cardiovascular system. In cardiomyocytes, anthracyclines are converted in a redox reduction through several NAD(P)H/H+-dependent enzymes (anthracycline-quinone to semiquinone). This reaction results in ROS formation, as does the interaction of anthracyclines with ionic iron. Oxidative modification of DNA, proteins, lipids results from ROS formation. Anthracyclines inhibit nuclear topoisomerase IIβ and cause DNA double strand breaks. In consequence, mitochondrial transcription factors (PGC1α/β) are reduced and mitochondrial biogenesis is impaired along with an impaired synthesis of contractile proteins. In mitochondria, anthracyclines through increased ROS formation damage mtDNA and increase opening of the mPTP, thus initiating apoptosis and cell death. Calcium overload results from anthracycline-induced opening of L-Type calcium channels and ryanodine receptors (RYR) of the sarcoplasmic reticulum. In the vasculature, anthracyclines reduce endothelial nitric oxide synthase activity and increase cytosolic calcium in smooth muscle cells, thus favoring vasoconstriction. Inhibition of the HER2 receptor by e.g. trastuzumab decreases a distinct kinase pathway and also increases the formation of ROS. Alkylating agents (e.g. cyclophosphamide) promote ROS formation and DNA damage. Likewise, ROS formation and DNA damage along with endothelial dysfunction and vasospasm result from 5-fluoruracil. (eNOS = endothelial NO synthase, NO = nitric oxide, cGMP = cyclic guanosine monophosphate, Ca2+ = calcium, ROS = reactive oxygen species, PGC1α/β = peroxisome proliferator activated receptor gamma co-activator α/β, O2 = oxygen, RAS = rat sarcoma (protein kinase), RAF = rapidly accelerated fibrosarcoma (protein kinase), MEK = mitogen activated protein kinase kinase, ERK = extracellular signal regulated kinase, PI3 = phosphoinositide 3-kinase, AKT = protein kinase B, Cyt C = cytochrome C, mPTP = mitochondrial permeability transition pore, mtDNA = mitochondrial DNA, RYR = ryanodine receptor, SR = sarcoplasmic reticulum).