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Anthracydine Cardiac toxicity aglycon

FIGURE 4.15 Elimination of the sugar moiety from anthracyclines.

Anthracydine Cardiac toxicity aglycon

FIGURE 4.15 Elimination of the sugar moiety from anthracyclines.

Another important chemical property of the anthracyclines relevant to their antitumor activity is their chelating ability due to the presence of p-hydroxycar-bonyl moieties in their structure, especially at the C-11 and C-12 positions.21 Probably because of ionic interactions with the phosphate groups, the anthracycline-Fe3+ chelate binds to DNA much more tightly than the anthracy-cline itself and can then generate Fe2+ by reaction with superoxide anion. As previously mentioned, Fe + cations thus generated in situ can form hydroxyl radicals through their Fenton reaction with hydrogen peroxide (Fig. 4.16). The high efficiency of DNA fragmentation by these hydroxyl radicals is reflected in the routine use of the Fenton reaction in DNA footprinting, a technique that fragments DNA indiscriminately and allows to determine where DNA-protein interactions take place.22

Anthracyclines also induce a severe dysregulation of iron homeostasis, possibly mediated by the release of iron from intracellular stores. This helps to explain why the Fenton reaction takes place in spite of the fact that cells normally have very little or no free iron available,23 and is also very important in explaining the cumulative cardiotoxicity of the anthracyclines. The main target responsible for this dysregulation of iron homeostasis by the anthracyclines seems to be aconitase, a Krebs cycle enzyme that reversibly isomerizes citrate to isocitrate and is characterized by a catalytic [4Fe-4S] cluster. The anthracycline-mediated release of one of the four Fe atoms from this cluster leads to loss of aconitase activity and converts the enzyme into an iron regulatory protein called (IRP-1). This protein

Fe3+

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