Doxorubicin-Dx Essay
2-Doxorubicin-DOX(Adriamycin): The anthracycline antibiotic doxorubicin (DOX) (C27H29NO11) (fig.2) (Kambas et al., 2013) is one of the most useful anticancer agents and is still a cornerstone in the therapy of many carcinoma types.(simunek et al ., 2009) including leukemia, lymphoma, breast, lung, ovarian, and liver cancers, among others. Originally isolated from the fungus streptomyces peucetius (youngmok,2003). Fig.( 3 )Chemical structure of doxorubicin (C27H29NO11). (Kambas et al., 2013)
Although DOX is an effective chemotherapeutic, dosage in patients is limited clinically due to severe cardiac toxicity (weinstein et al …show more content…
Dexrazoxane is an iron chelator that is structurally similar to EDTA; however, dexrazoxane has additional effects as described below that obscure a simple conclusion that iron chelation alone is responsible for cardioprotection. 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 cardiotoxicity . 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 cardiomyocytes. Cardiomyocytes lacking Top2b did not exhibit transcriptional patterns associated with doxorubicin-mediated
Although DOX is an effective chemotherapeutic, dosage in patients is limited clinically due to severe cardiac toxicity (weinstein et al …show more content…
Dexrazoxane is an iron chelator that is structurally similar to EDTA; however, dexrazoxane has additional effects as described below that obscure a simple conclusion that iron chelation alone is responsible for cardioprotection. 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 cardiotoxicity . 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 cardiomyocytes. Cardiomyocytes lacking Top2b did not exhibit transcriptional patterns associated with doxorubicin-mediated