Efficacy of melatonin, mercaptoethylguanidine and 1400W in doxorubicin- and trastuzumab-induced cardiotoxicity.
Doxorubicin (DOX) and Trastuzumab (TRAST) are effective agents for the treatment of many neoplastic diseases. Cardiotoxicity is a major side effect of these drugs and limit their use. In this study, the possible protective effects of melatonin (MEL), mercaptoethylguanidine (MEG), or N-(3-(aminomethyl) benzyl) acetamidine (1400W) against the cardiotoxicity of DOX and TRAST were tested. Male Sprague-Dawley rats received an injection of DOX (20 mg/kg) alone or in combination with TRAST (10 mg/kg) to induce cardiotoxicity; daily treatments with MEL (10 mg/kg × 2), MEG (10 mg/kg × 2), or 1400W (10 mg/kg × 2) were begun 36 hr before and continued for 72 hr after DOX and TRAST administration. Oxidant/antioxidant indices of the cardiac tissue, namely, malondialdehyde, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), as well as serum levels of creatine phosphokinase (CK-MB) were measured. Additionally, the injury scores were evaluated histopathologically. Malondialdehyde levels were significantly higher, while SOD and GSH-Px activities were significantly reduced in rats with DOX- or DOX+TRAST-induced cardiotoxicity compared to normal values. All three treatment agents significantly reversed oxidative stress markers. Serum CK-MB levels were significantly increased after treatment with DOX and DOX+TRAST; these changes were also reversed by each of the treatments and resulted in near normal levels. Both the DOX- and DOX+TRAST-treated rats presented similar histopathologic injuries; in the animals treated with the protective agents, histologic protection of the cardiac tissue was apparent. These results suggested that MEL, MEG, as well as 1400 W are effective in preventing DOX- or DOX+TRAST-induced cardiotoxicity.
Department of Medical Oncology, Gulhane Military Medical Academy, Ankara, Turkey.
Mustafa
M
Ozturk
Mehmet
M
Ozler
Yasemin Gulcan
YG
Kurt
Bekir
B
Ozturk
Bulent
B
Uysal
Nail
N
Ersoz
Mehmet
M
Yasar
Seref
S
Demirbas
Bulent
B
Kurt
Cengizhan
C
Acikel
Yesim
Y
Oztas
Fikret
F
Arpaci
Turgut
T
Topal
Ahmet
A
Ozet
Selmin
S
Ataergin
Okan
O
Kuzhan
Sukru
S
Oter
Ahmet
A
Korkmaz
D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D001596:Benzylamines / Q000494:pharmacology*; D003402:Creatine Kinase / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D005979:Glutathione Peroxidase / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008550:Melatonin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism; D000068878:Trastuzumab
D000578:Amidines; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001596:Benzylamines; D006146:Guanidines; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D008315:Malondialdehyde; D004317:Doxorubicin; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D003402:Creatine Kinase; D008550:Melatonin; D000068878:Trastuzumab; C100078:2-mercaptoethylguanidine