[Effect of herceptin combined with Doxorubicin on rat cardiotoxicity].
OBJECTIVE
Herceptin is a humanized monoclonal antibody for treating the patients with metastatic breast cancers overexpressing human epidermal growth factor receptor (HER-2). Herceptin combined with doxorubicin 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 were randomized into four groups (n=9): control group, Herceptin group, doxorubicin group, Herceptin combined with doxorubicin group. The value of malon dialdehyde (MDA) was measured by thiobarbituric acid (TBA) method and the activity of glutathione peroxidase (GSH-Px) was measured by 5,5'-dithiobis-2-nitrobenzoic acid (DTNB) method. The damage and apoptosis of myocardium were observed by electron microscopy and tdt-mediated dUTP nick end labeling (TUNEL). The ratio of myocardial apoptosis cells was quantified using flow cytometry.


RESULTS
The value of MDA in control group and Herceptin group were (0.70+/-0.03) and (0.73+/-0.05) nmol x(mg x protein)(-1), respectively; the activity of GSH-PX in control group and Herceptin group were (81.31+/-0.13) and (78.43+/-0.15) U x(mg x protein)(-1),respectively;the two groups were similar. The value of MDA in doxorubicin group and Herceptin combined with doxorubicin group were (0.88+/-0.10) and (0.94+/-0.13) nmol x(mg x 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 x(mg x protein)(-1),respectively. The most prominent 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 myocardial cells from (5.35+/-0.27) % in doxorubicin group to (8.27+/-0.38) % in Herceptin combined with doxorubicin group as measured by flow cytometry (P< 0.05).


CONCLUSIONS
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.
Xu
Yang
Y
Department of Oncology, Changhai Hospital, The second Military Medical University, Shanghai, 200433, PR China. hebinxuyang@yahoo.com.cn
He
Bin
B
Wang
Ya-Jie
YJ
Fu
Qiang
Q
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000633:toxicity*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D005979:Glutathione Peroxidase / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D008315:Malondialdehyde / Q000032:analysis; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D008315:Malondialdehyde; D004317:Doxorubicin; D005979:Glutathione Peroxidase; D000068878:Trastuzumab