The receptor tyrosine kinase epidermal growth factor receptor erbB2 is the target of trastuzumab, the B10 monoclonal antibody. When used with breast cancers overexpressing erbB2, the B10 treatment provides significant gains in survival but also increased risks for hypokinetic cardiomyopathy and heart failure. If patients had been pretreated with anthracycline chemotherapeutics, the incidence and severity of trastuzumab-induced cardiomyopathy would have been dramatically increased. It has been hypothesized that the anthracyclines promote a protective effect mediated by erbB2 and that the B10 antibody blocks that effect. In this issue, Spallarossa et al., studied the effects of low doses of anthracyclines, an antibody to ErbB2 or an antioxidant, on neonatal cardiomyocytes and on the H9c2 cell line in culture. The results show that low-dose epirubicin anthracycline caused senescence that was switched to apoptosis with subsequent exposure to the B10 antibody. The toxicity of epirubicin was largely mediated by activation of NAD(P)H oxidase activation, and the erbB2 overexpression due to epirubicin is a redox stress response. Coadministration of the antioxidant and iron-chelating dexrazoxane with epirubicin before treatment with B10 provided a remarkable degree of protection. The idea to study cellular senescence in cardiomyocytes might seem odd because cardiomyocytes are terminally differentiated. However, a new view on senescence in cardiomyocytes was introduced with the recent demonstration that senescence-like changes in cardiomyocytes are caused by low doses of doxorubicin. Thus, the results are of interest to biologists, pharmacologists, and clinical oncologists and suggest that early dexrazoxane treatment of breast cancer patients who receive anthracyclines before trastuzumab might reduce the incidence of cardiotoxicity.
See article at J Pharmacol Exp Ther 2010, 332:87–96.
- © 2010 by The American Society for Pharmacology and Experimental Therapeutics