Anthracycline cardiotoxicity

作者：Menna Pierantonio; Salvatorelli Emanuela; Gianni Luca; Minotti Giorgio^*

来源：ANTHRACYCLINE CHEMISTRY AND BIOLOGY II: MODE OF ACTION, CLINICAL ASPECTS AND NEW DRUGS , SPRINGER-VERLAG BERLIN, HEIDELBERGER PLATZ 3, D-14197 BERLIN, GERMANY, 21-44, 2008.

DOI：10.1007/128_2007_11

• analogs
• anthracyclines
• cardiotoxicity
• metabolism
• pharmacokinetics

The clinical use of doxorubicin and other quinone-hydroquinone anticancer anthracyclines is limited by a dose-related cardiotoxicity. Here, we review the correlation of cardiotoxicity of doxorubicin with its peak plasma concentration and diffusion in the heart, followed by reductive bioactivation or oxidative inactivation. One-electron quinone reduction and two-electron side chain carbonyl reduction are accompanied by iron and free radical reactions that are responsible for many aspects of anthracycline cardiotoxicity. In contrast, one-electron hydroquinone oxidation serves as a salvage pathway for degrading and detoxifying anthracyclines. Mechanism-based cardioprotective strategies therefore involve replacing bolus administration with slow infusions (to reduce the drug's plasma peak), encapsulating anthracyclines in liposomes (to reduce the drug's cardiac diffusion), and administering antioxidants or iron chelators. Preclinical modelling and clinical studies suggest that eliminating the side chain carbonyl group reduction warranted a satisfactory degree of cardioprotection. Approved or investigational anthracyclines that lacked the carbonyl group or showed an inherent resistance to carbonyl reduction might prove safer than doxorubicin, particularly when administered with new generation drugs that otherwise caused a toxic synergism with doxorubicin.

• 出版日期2008