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Anti-inflammatory agents and monoHER protect against DOX-induced cardiotoxicity and accumulation of CML in mice.
Br J Cancer 2007; 96(6):937-43BJ

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. Nepsilon-(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. Nepsilon-(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 (P<or=0.02). 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. Nepsilon-(carboxymethyl) lysine positivity was significantly reduced (P<or=0.01) 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.

Authors+Show Affiliations

Department of Medical Oncology, VU University Medical Center, 1081 HV Amsterdam, the Netherlands. ame.bruynzeel@vumc.nlNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17325706

Citation

Bruynzeel, A M E., et al. "Anti-inflammatory Agents and monoHER Protect Against DOX-induced Cardiotoxicity and Accumulation of CML in Mice." British Journal of Cancer, vol. 96, no. 6, 2007, pp. 937-43.
Bruynzeel AM, Abou El Hassan MA, Schalkwijk C, et al. Anti-inflammatory agents and monoHER protect against DOX-induced cardiotoxicity and accumulation of CML in mice. Br J Cancer. 2007;96(6):937-43.
Bruynzeel, A. M., Abou El Hassan, M. A., Schalkwijk, C., Berkhof, J., Bast, A., Niessen, H. W., & van der Vijgh, W. J. (2007). Anti-inflammatory agents and monoHER protect against DOX-induced cardiotoxicity and accumulation of CML in mice. British Journal of Cancer, 96(6), pp. 937-43.
Bruynzeel AM, et al. Anti-inflammatory Agents and monoHER Protect Against DOX-induced Cardiotoxicity and Accumulation of CML in Mice. Br J Cancer. 2007 Mar 26;96(6):937-43. PubMed PMID: 17325706.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Anti-inflammatory agents and monoHER protect against DOX-induced cardiotoxicity and accumulation of CML in mice. AU - Bruynzeel,A M E, AU - Abou El Hassan,M A, AU - Schalkwijk,C, AU - Berkhof,J, AU - Bast,A, AU - Niessen,H W M, AU - van der Vijgh,W J F, Y1 - 2007/02/27/ PY - 2007/2/28/pubmed PY - 2007/5/9/medline PY - 2007/2/28/entrez SP - 937 EP - 43 JF - British journal of cancer JO - Br. J. Cancer VL - 96 IS - 6 N2 - 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. Nepsilon-(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. Nepsilon-(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 (P<or=0.02). 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. Nepsilon-(carboxymethyl) lysine positivity was significantly reduced (P<or=0.01) 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. SN - 0007-0920 UR - https://www.unboundmedicine.com/medline/citation/17325706/Anti_inflammatory_agents_and_monoHER_protect_against_DOX_induced_cardiotoxicity_and_accumulation_of_CML_in_mice_ L2 - http://dx.doi.org/10.1038/sj.bjc.6603640 DB - PRIME DP - Unbound Medicine ER -