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Preclinical animal models of cardiac protection from anthracycline-induced cardiotoxicity
1Division of Applied Pharmacology Research, Center for Drug Evaluation and Research, Food and Drug Administration, Laurel, MD 20708, USA.
Abstract:
The chronic cardiotoxic effects of anthracyclines were initially detected in clinical trials with daunorubicin and doxorubicin. The clinical importance of anthracycline-induced chronic cardiotoxicity has led to the development of several animal models of this syndrome. Animal species examined in detail as models of this cardiac toxicity include the rabbit, the normotensive and spontaneously hypertensive rat, the mouse, the pig, and the dog. The advantages and disadvantages of these animal models differ according to species: small animals can be used for comparative investigations of anthracycline analogues and/or protectors, which may be available only in limited amounts, while large animals can be used for studies in which evaluation of cardiac function are to be made. Among the various animals examined, the spontaneously hypertensive rat and the beagle dog are considered the most suitable small and large animal models, respectively, because of the reproducibility of the lesions induced by anthracyclines in the two species. A variety of pharmacologic agents has been tested for cardioprotective activity. The most successful of these agents are those that function as antioxidants, because they either scavenge reactive oxygen species or prevent their formation. The most clinically useful of these agents is ICRF-187 (dexrazoxane), which has been found to be cardioprotective in all animal models.
Insights
Anthracycline chemotherapy can cause chronic heart damage. Animal models, particularly the spontaneously hypertensive rat and beagle dog, help study this cardiotoxicity and test protective drugs like ICRF-187 (dexrazoxane).
Area of Science:
- Pharmacology
- Cardiology
- Toxicology
Background:
- Anthracyclines (e.g., daunorubicin, doxorubicin) are known to cause chronic cardiotoxicity.
- This cardiotoxicity is a significant clinical concern, necessitating robust preclinical research.
- Several animal models have been developed to study this phenomenon.
Purpose of the Study:
- To review and compare various animal models used for studying anthracycline-induced cardiotoxicity.
- To identify the most suitable animal models for preclinical research on cardiotoxicity and cardioprotection.
- To discuss the efficacy of pharmacologic agents, particularly antioxidants, in preventing anthracycline cardiotoxicity.
Main Methods:
- Review of existing literature on animal models of anthracycline cardiotoxicity.
- Comparison of advantages and disadvantages of different animal species (rabbit, rat, mouse, pig, dog).
- Evaluation of pharmacologic agents tested for cardioprotective effects.
Main Results:
- Spontaneously hypertensive rats and beagle dogs are identified as the most suitable small and large animal models, respectively, due to reproducible lesions.
- Antioxidant agents are the most successful in mitigating anthracycline cardiotoxicity by scavenging reactive oxygen species.
- ICRF-187 (dexrazoxane) demonstrated consistent cardioprotective activity across all tested animal models.
Conclusions:
- Animal models are crucial for understanding and managing anthracycline cardiotoxicity.
- The spontaneously hypertensive rat and beagle dog offer reliable platforms for preclinical studies.
- ICRF-187 (dexrazoxane) represents a clinically useful cardioprotective agent against anthracycline-induced cardiac damage.