1. ¹Department of Medical Oncology, VU University Medical Center, 1081 HV Amsterdam, the Netherlands
2. ²Cancer Biology Department, National Cancer Institute, Cairo, Egypt
3. ³Department of Internal Medicine, University of Maastricht, 6200 MD Maastricht, the Netherlands
4. ⁴Department of Clinical Epidemiology and Biostatistics, VU University Medical Center, 1081 HV Amsterdam, the Netherlands
5. ⁵Department of Pharmacology and Toxicology, Faculty of Medicine, University of Maastricht, 6200 MD Maastricht, the Netherlands
6. ⁶Department of Pathology, VU University Medical Center, 1081 HV Amsterdam, the Netherlands
7. ⁷ICaR-VU, VU University Medical Center, 1081 HV Amsterdam, the Netherlands
8. ⁸Department of Cardiac Surgery, VU University Medical Center, 1081 HV Amsterdam, the Netherlands

Correspondence: Dr AME Bruynzeel, E-mail: ame.bruynzeel@vumc.nl

Revised 10 January 2007; Accepted 25 January 2007; Published online 27 February 2007.

Abstract

Cardiac damage is the major limiting factor for the clinical use of doxorubicin (DOX). Preclinical studies indicate that inflammatory effects may be involved in DOX-induced cardiotoxicity. N-(carboxymethyl) lysine (CML) is suggested to be generated subsequent to oxidative stress, including inflammation. Therefore, the aim of this study was to investigate whether CML increased in the heart after DOX and whether anti-inflammatory agents reduced this effect in addition to their possible protection on DOX-induced cardiotoxicity. These effects were compared with those of the potential cardioprotector 7-monohydroxyethylrutoside (monoHER). BALB/c mice were treated with saline, DOX alone or DOX preceded by ketoprofen (KP), dexamethasone (DEX) or monoHER. Cardiac damage was evaluated according to Billingham. N-(carboxymethyl) lysine was quantified immunohistochemically.

Compared to saline, a 21.6-fold increase of damaged cardiomyocytes was observed in mice treated with DOX (P<0.001). Addition of KP, DEX or monoHER before DOX significantly reduced the mean ratio of abnormal cardiomyocytes in comparison to mice treated with DOX alone (P0.02). In addition, DOX induced a significant increase in the number of CML-stained intramyocardial vessels per mm² (P=0.001) and also in the intensity of CML staining (P=0.001) compared with the saline-treated group. N-(carboxymethyl) lysine positivity was significantly reduced (P0.01) by DOX-DEX, DOX-KP and DOX-monoHER. These results confirm that inflammation plays a role in DOX-induced cardiotoxicity, which is strengthened by the observed DOX-induced accumulation of CML, which can be reduced by anti-inflammatory agents and monoHER.