الفهرس 
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Abstract
chemotherapy (DOX) is accompanied by various side effects such as vomiting, diarrhoea, anorexia, lethargy, fever, alopecia, anaemia, neutropenia etc. (Sorenmo,2003).
2.1-Mechanism of action of DOX:
Doxorubicin has been extensively studied, and doxorubicin its metabolites generate a variety of cellular effects leading to generation of reactive oxygen species (ROS), changes in iron metabolism, and changes in (Ca2+)signaling (Fig.3) (Karin et al.,2014). ROS generation through redox cycling and the importance of iron in these processes have been the areas of major emphasis.
The twoimportant hypotheses that have guided our current thinkingon doxorubicin cytotoxicity; (i) the hypothesis that chelation of iron could reduce toxicity has led to the acceptance of dexrazoxane as an important clinically useful protective agent (Doroshow,2012). Dexrazoxane is an iron chelator that is structurally similar to EDTA; however, In addition to iron chelation, dexrazoxane is a catalytic inhibitor of DNAtopoisomerase II (Top2). Doxorubicin is a potent inhibitor of (Top2), and causes the trapping of the enzyme on DNA as a covalent complex. Because a substantial body of evidence suggests that topoisomerase-mediated damage is a critical determinant of tumor cell killing (Nitiss,2009), could topoisomerase II be related to doxorubicin toxicity. Treatment of nondividing cells with dexrazoxane leads to depletion of (Top2b), the only (Top2) isoform that is normally expressed in nondividing cells (and therefore the only Top2 isoform in cardiomyocytes). Therefore, dexrazoxane leads to the elimination of (Top2b), and prevents trapping of the enzyme on DNA.
These observations were explored further in a mouse model in which Top2b was selectively depleted in myocytes. myocytes lacking Top2b did not exhibit transcriptional patterns associated with doxorubicin-mediated damage, and importantly, showed reduced levels of mitochondrial damage and reduced toxicity (Wallace,2007). To reconcile these hypotheses, it is helpful to note that one major area of consensus is that both short-term and chronic toxicity of doxorubicin are most clearly seen in effects on mitochondria.
Therefore, an appealing(ii) hypothesis is that DOX induces toxicity through effects on mitochondrial DNA and generation of free radicals,modification of cardiac geneexpression, alteration of calcium exchange, lipidperoxidation inducing a mitochondrial membranedysfunction, and myocyte apoptosis. Mitochondrial DNA encodes a small number of proteins that are critical for oxidative phosphorylation, and the RNAs that make up the mitochondrial ribosome. All other components of the mitochondrial ”genome” are encoded in the nucleus. Proteins destined for the mitochondrion that are encoded by the nucleus include a mitochondrial DNA polymerase, other proteins needed for DNA metabolism, transcription proteins, ribosomal proteins, and some of the proteins critical for oxidative phosphorylation. DNA metabolic proteins encoded by the nucleus include a type (1B topoisomerase) that seems to be specific for mitochondria and two other topoisomerases, (Top3a) (a type 1A topoisomerase that has functions distinct from other topoisomerases) and (Top2b) With these considerations in mind, we can reconsider the effects of doxorubicin specifically on mitochondrial DNA. By redox and iron-dependent mechanisms, ROS will generate lesions in mitochondrial DNA. Oxidative lesions will block mitochondrial transcription and replication and are likely also to affect retrograde signaling from the mitochondrion to the nucleus.
Alternatively, because mitochondria contain (Top2b), doxorubicin.