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《Chinese Journal of Cancer》 2004-04
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Effect of Herceptin Combined with Doxorubicin on Rat Cardiotoxicity

Xu Yang1, He Bin2, Wang Ya- Jie1, Fu Qiang1 1. Department of Oncology, Changhai Hospital,The second Military Medical University, Shanghai,200433, P.R.China 2. Department of Cardiothoracic Surgery,Changhai Hospital,The Second Military Medical University, Shanghai,200433, P.R.China  
BACKGROUND OBJECTIVE: Herceptin is a humanized monoclonal a nt ibody for treating the patients with metastatic breast cancers overexpressing h uman epidermal growth factor receptor (HER- 2). Herceptin combined with doxorub icin markedly increased the incidence of cardiac dysfunction in clinical trials. The current study was designed to investigate the cardiotoxicity aggravated by Herceptin combined with doxorubicin in rats. METHODS: Thirty- six female rats w ere randomized into four groups (n=9): control group, Herceptin group, doxorubic in group, Herceptin combined with doxorubicin group. The value of malon dialdehy de (MDA) was measured by thiobarbituric acid (TBA) method and the activity of gl utathione peroxidase (GSH- Px) was measured by 5,5′ - dithiobis- 2- nitrobe nzoic acid (DTNB) method. The damage and apoptosis of myocardium were observed b y electron microscopy and tdt- mediated dUTP nick end labeling (TUNEL). The rat io of myocardial apoptosis cells was quantified using flow cytometry. RESULTS: T he value of MDA in control group and Herceptin group were (0.70± 0.03) and (0.7 3± 0.05) nmol· (mg· protein)- 1, respectively; the activity of GSH- PX in c ontrol group and Herceptin group were (81.31± 0.13) and (78.43± 0.15) U· (mg · protein)- 1,respectively;the two groups were similar. The value of MDA in do xorubicin group and Herceptin combined with doxorubicin group were (0.88± 0.10) and (0.94± 0.13) nmol· (mg· protein)- 1, respectively; the activity of GSH - PX in doxorubicin group and Herceptin combined with doxorubicin group were(67 .88± 0.24) and(63.37± 0.28) U· (mg· protein)- 1,respectively. The most prom inent ultrastructural damages were mitochondrial swelling with fragmentation of cristae and vacuoles formation in doxorubicin group and Herceptin combined with doxorubicin group. Herceptin markedly increased the ratio of apoptosis of myocar dial cells from (5.35± 0.27) % in doxorubicin group to (8.27± 0.38) % in H erceptin combined with doxorubicin group as measured by flow cytometry (P 0.05) . CONCLUSION: Herceptin alone had little toxic effects on rat cardiomocytes, but Herceptin combined with doxorubicin can aggravate rat cardiotoxicity. Herceptin can also increase the number of the apoptosis cell in rat myocardium.
【CateGory Index】: R96
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