Long-term and short-term models for studying anthracycline cardiotoxicity and protectors
- Jacques Robert
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The clinical importance of the cardiotoxicity of anthracyclines requires the availability of preclinical models able to predict the cardiotoxicity of novel anthracycline analogs in reference to doxorubicin or of cardioprotectors aimed at circumventing the deleterious effects of these drugs. The reference model has been defined long ago and has proven its validity. Weanling rabbits given weekly injections of doxorubicin for 4 months developed a cardiomyopathy, which can be assessed from a clinical and pathological point of view. Models in other animals such as rats or mice were similarly implemented, also with long-term exposures to the drug, resulting in cardiac failure and severe pathological alterations, which could be graded for comparison. Starting from the evidence that the damage caused by anthracyclines on cardiomyocytes was immediate after each injection and that the functional efficiency of the myocardium should be affected long before the morphological alterations become detectable, we developed a short-term model studying the cardiac performances of isolated perfused hearts of rats that had been treated within 12 days by repetitive administrations of the molecule(s) to be tested. This model provided the data expected from clinical experience: epirubicin appeared less cardiotoxic than doxorubicin; liposomal formulations appeared less cardiotoxic than free drug formulations; dexrazoxane strongly protected against doxorubicin cardiotoxicity. We were then able to show that paclitaxel could potentialize doxorubicin cardiotoxicity, but that docetaxel did not so; or that a high dose of dexrazoxane brought significantly higher protection than a conventional dose. Based upon these contributions, we can encourage the use of the short-term model of isolated perfused rat heart to screen the preclinical cardiotoxicity of anthracycline molecules, formulations and combinations.
- Shan, K., Lincoff, A. M., & Young, J. B. (1996). Anthracycline-induced cardiotoxicity. Annals of Internal Medicine, 125, 47–58.
- Rhoden, W., Hasleton, P., & Brooks, N. (1993). Anthracyclines and the heart. British Heart Journal, 70, 499–502.
- Pein, F., Sakiroglu, O., Dahan, M., Lebidois, J., Merlet, P., Shamsaldin, A., Villain, E., de Vathaire, F., Sidi, D., & Hartmann, O. (2004). Cardiac abnormalities 15 years and more after adriamycin therapy in 229 childhood survivors of a solid tumour at the Institut Gustave Roussy. British Journal of Cancer, 91, 37–44. CrossRef
- Herman, E. H., & Ferrans, V. (1986). Pretreatment with ICRF-187 provides long-lasting protection against chronic daunorubicin cardiotoxicity in rabbits. Cancer Chemotherapy and Pharmacology, 16, 102–106. CrossRef
- van Acker, F. A., Hulshof, J. W., Haenen, G. R., Menge, W. M., van der Vijgh, W. J., & Bast, A. (2001). New synthetic flavonoids as potent protectors against doxorubicin-induced cardiotoxicity. Free Radical Biology and Medicine, 31, 31–37. CrossRef
- Herman, E. H., Zhang, J., Lipshultz, S. E., Rifai, N., Chadwick, D., Takeda, K., Yu, Z. X., & Ferrans, V. J. (1999). Correlation between serum levels of cardiac troponin-T and the severity of the chronic cardiomyopathy induced by doxorubicin. Journal of Clinical Oncology, 17, 2237–2243.
- Maral, R., Bourat, G., Ducrot, R., Fournel, J., Ganter, P., Julou, L., Koenig, F., Myon, J., Pascal, S., Pasquet, J., Populaire, P., de Ratuld, Y., & Werner, G. H. (1967). Toxicologic study and experimental antitumor activity of rubidomycin (13,057 R.P.). Pathologie et Biologie, 15, 903–908.
- Jaenke, R. S. (1974). An anthracycline antibiotic-induced cardiomyopathy in rabbits. Laboratory Investigation, 30, 292–304.
- Ferrans, V. J., Sanchez, J. A., & Herman, E. H. (1992). Pathologic anatomy of animal models of anthracycline-induced cardiotoxicity. In F. M. Muggia, M. D. Green, & J. L. Speyer (Eds.), Cancer treatment and the heart (pp. 89–113). Baltimore, MD: The Johns Hopkins University Press.
- Van Vleet, J. F., Greenwood, L., Ferrans, V. J., & Rebar, A. H. (1978). Effect of selenium-vitamin E on adriamycin-induced cardiomyopathy in rabbits. American Journal of Veterinary Research, 39, 997–1010.
- Herman, E. H., Ferrans, V. J., Jordan, W., & Ardalan, B. (1981). Reduction of chronic daunorubicin cardiotoxicity by ICRF-187 in rabbits. Research Communications in Chemical Pathology and Pharmacology, 31, 85–97.
- Herman, E. H., el-Hage, A. N., Ferrans, V. J., & Ardalan, B. (1985). Comparison of the severity of the chronic cardiotoxicity produced by doxorubicin in normotensive and hypertensive rats. Toxicology and Applied Pharmacology, 78, 202–214. CrossRef
- Pouna, P., Bonoron-Adèle, S., Gouverneur, G., Tariosse, L., Besse, P., & Robert, J. (1995). Evaluation of anthracycline cardiotoxicity with the model of isolated, perfused rat heart: comparison of new analogues versus doxorubicin. Cancer Chemotherapy and Pharmacology, 35, 257–261. CrossRef
- Pouna, P., Bonoron-Adèle, S., Gouverneur, G., Tariosse, L., Besse, P., & Robert, J. (1996). Development of the model of rat isolated perfused heart for the evaluation of anthracycline cardiotoxicity and its circumvention. British Journal of Pharmacology, 117, 1593–1599.
- Platel, D., Pouna, P., Bonoron-Adèle, S., & Robert, J. (1999). Comparative cardiotoxicity of idarubicin and doxorubicin using the isolated perfused rat heart model. Anticancer Drugs, 10, 671–676. CrossRef
- Platel, D., Bonoron-Adèle, S., Dix, R. K., & Robert, J. (1999). Preclinical evaluation of the cardiac toxicity of HMR-1826, a novel prodrug of doxorubicin. British Journal of Cancer 81, 24–27. CrossRef
- Platel, D., Pouna, P., Bonoron-Adèle, S., & Robert, J. (2000). Preclinical evaluation of the cardiotoxicity of taxane-anthracycline combinations using the model of isolated perfused rat heart. Toxicology and Applied Pharmacology, 163, 135–140. CrossRef
- Plandé, J., Platel, D., Tariosse, L., & Robert, J. (2006). Experimental study of dexrazoxane-anthracycline combinations using the model of isolated perfused rat heart. Toxicology Letters, 161, 37–42. CrossRef
- Long-term and short-term models for studying anthracycline cardiotoxicity and protectors
Volume 7, Issue 2 , pp 135-139
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- Cancer chemotherapy
- Rat isolated perfused heart
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- Jacques Robert (1) (2)
- Author Affiliations
- 1. Université Victor Segalen Bordeaux, Institut Bergonié, Bordeaux-Cedex, France
- 2. Laboratoire de Pharmacologie des Agents Anticancéreux, Institut Bergonié, 229 Cours de l’Argonne, 33076, Bordeaux-Cedex, France