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Absence of cardiotoxicity of the experimental cytotoxic drug cyclopentenyl cytosine (CPEC) in rats

  • Organ Toxicity and Mechanisms
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Abstract

The experimental anticancer drug cyclopentenyl cytosine (CPEC) was associated with cardiotoxicity in a phase I study. The aim of the present study was twofold; first we investigated whether the observed effects could be reproduced in in-vitro and in-vivo rat models. Second, we intended to investigate the underlying mechanism of the possible cardiotoxicity of CPEC. Effects on frequency and contractility were studied on the isolated atria of 18 male Wistar rats. Atria were incubated with 0.1 mmol L−1 (n=6) or 1 mmol L−1 (n=6) CPEC for 1.5 h and compared with control atria (incubation with buffer solution, n=6). The cardiac apoptosis-inducing potential was studied in-vivo on 66 rats by 99mTc-Annexin V scintigraphy, followed by postmortem determination of radioactivity in tissues, histological confirmation with the TUNEL assay (late-phase apoptosis), and immunohistochemical staining for cleaved caspase 3 and cytochrome C (early-phase apoptosis). Serum levels of the necrotic cardiomyopathy marker troponin T were also determined. No effect on heart frequency was found in the isolated atria after CPEC treatment. A trend towards a decrease of contraction force was observed. However, the differences were not statistically significant. 99mTc-Annexin V scintigraphy showed no increase in cardiac uptake ratio upon CPEC treatment in the in-vivo rat model, which was confirmed by determination of radioactivity in heart versus blood ratios. At each section a few individual isolated late apoptotic cells (<5) could be identified by the TUNEL assay in the highest CPEC dose group (90 mg kg−1) but not in controls or in rats treated with 60 mg kg−1 CPEC. Staining for the early apoptosis markers cleaved caspase 3 and cytochrome C did not reveal any significant differences between treated and control rats. Cardiac troponin T levels were not increased after CPEC treatment. CPEC does not affect heart frequency or contraction force in our cardiotoxicity models. Moreover, we did not find an indication of CPEC-induced apoptosis in heart tissue.

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Acknowledgements

Dr M van den Hoff is financially supported by The Netherlands Heart Foundation (grant M96.003). The animal studies were performed after approval of the Ethical Animal Research Committee of the University of Amsterdam and following its guidelines.

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Authors and Affiliations

  1. Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Albinusdreef 2, Postbox 9600, 2300, RC, Leiden, The Netherlands

    Kirsten Schimmel & Henk-Jan Guchelaar

  2. Department of Nuclear Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands

    Roel Bennink & Kora de Bruin

  3. Laboratory of Genetic Metabolic Diseases, Academic Medical Centre, University of Amsterdam, The Netherlands

    Rene Leen & André van Kuilenburg

  4. Department of Pharmacology and Pharmacotherapy, Academic Medical Centre, University of Amsterdam, The Netherlands

    Karsten Sand & Martin Pfaffendorf

  5. Department of Anatomy and Embryology, Molecular and Experimental Cardiology Group, Academic Medical Centre, University of Amsterdam, The Netherlands

    Maurice van den Hoff

  6. Theseus Imaging Division, North American Scientific, Boston, MA, USA

    Jean-Luc Vanderheyden & Neil Steinmetz

  7. Department of Pediatric Oncology, Academic Medical Centre, University of Amsterdam, The Netherlands

    Arnauld Verschuur

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  1. Kirsten Schimmel
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  2. Roel Bennink
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  3. Kora de Bruin
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  4. Rene Leen
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  6. Maurice van den Hoff
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  8. Jean-Luc Vanderheyden
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  12. Henk-Jan Guchelaar
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Correspondence to Kirsten Schimmel.

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Schimmel, K., Bennink, R., de Bruin, K. et al. Absence of cardiotoxicity of the experimental cytotoxic drug cyclopentenyl cytosine (CPEC) in rats. Arch Toxicol 79, 268–276 (2005). https://doi.org/10.1007/s00204-004-0633-5

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  • DOI: https://doi.org/10.1007/s00204-004-0633-5

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