Related Experiment Videos
Effects of three new anthracyclines and doxorubicin on the rat isolated heart
Z M Chen1, T Colombo, L Conforti
1Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Abstract:
The acute cardiac toxicity of three second-generation anthracycline analogues and doxorubicin was compared in a model of the rat isolated Langendorff perfused heart. The drugs, doxorubicin (DX), 4-epi-doxorubicin (4'EDX), 4-demethoxy-daunorubicin (4DMDR) and 4'-deoxy-doxorubicin (4'dxDX) were infused for 40 min at a concentration of 26 microM into the isolated hearts. All four compounds significantly reduced cardiac work and its first derivative. The time to 50% decrease in work (TW50) was respectively 36, 23, 9 and 7 min for DX, 4'EDX, 4'dxDX and 4DMDR. The three anthracycline derivatives, but not DX, significantly increased coronary resistance. Heart rate was reduced by all compounds compared with baseline, but not compared with controls. Rhythm disturbances were seen with all five hearts perfused with 4DMDR, which stopped beating before 40 min; 2/5 hearts in the 4'EDX group and 1/5 hearts in the 4'dxDX group also stopped before the end of perfusion. All the compounds reached concentrations in the myocardium 8 to 50 times higher than in the perfusing medium. The more cardiotoxic the compound, the higher was its myocardial concentration; a significant correlation was found for all four agents. Noradrenaline was never measurable in the perfusate of control and DX hearts; perfusion with the three anthracycline derivatives caused some release, but the pattern was not clearcut and the maximum concentrations attained in the perfusate were relatively low (less than or equal to 1.6 X 10(-9) M). In conclusion, in the rat isolated perfused heart, the early cardiotoxicity induced by equimolar concentrations of the three anthracycline compounds was greater than that induced by DX and was directly related to drug accumulation in the myocardium. Catecholamines do not seem to have a major role in the development of toxicity in this model.
Insights
New anthracycline analogues show greater early cardiotoxicity than doxorubicin (DX) in rat hearts. This increased toxicity correlates with higher drug accumulation in the myocardium, suggesting a direct relationship between myocardial concentration and cardiotoxicity.
Area of Science:
- Cardiology
- Pharmacology
- Toxicology
Background:
- Anthracyclines are widely used chemotherapy agents.
- Cardiotoxicity is a significant dose-limiting side effect of anthracycline therapy.
- Second-generation anthracycline analogues are developed to improve efficacy and reduce toxicity.
Purpose of the Study:
- To compare the acute cardiac toxicity of doxorubicin (DX) and three second-generation anthracycline analogues.
- To investigate the relationship between drug accumulation in the myocardium and cardiotoxicity.
- To assess the role of catecholamines in anthracycline-induced cardiotoxicity.
Main Methods:
- Utilized the rat isolated Langendorff perfused heart model.
- Administered equimolar concentrations (26 microM) of DX, 4-epi-doxorubicin (4'EDX), 4-demethoxy-daunorubicin (4DMDR), and 4'-deoxy-doxorubicin (4'dxDX) for 40 minutes.
- Measured cardiac work, coronary resistance, heart rate, rhythm disturbances, and myocardial drug concentrations.
Main Results:
- All four compounds significantly reduced cardiac work.
- The time to 50% decrease in work (TW50) was shortest for 4DMDR (7 min) and 4'dxDX (9 min), followed by 4'EDX (23 min) and DX (36 min).
- 4DMDR, 4'EDX, and 4'dxDX significantly increased coronary resistance and induced rhythm disturbances, with some hearts stopping before 40 minutes.
- Myocardial drug concentrations were 8-50 times higher than perfusate concentrations, correlating directly with cardiotoxicity.
- Catecholamine release was minimal and not clearly linked to toxicity.
Conclusions:
- Second-generation anthracycline analogues exhibited greater early cardiotoxicity than doxorubicin at equimolar concentrations in this model.
- Cardiotoxicity is directly related to the accumulation of these anthracycline compounds within the myocardium.
- Catecholamines do not appear to play a major role in the acute cardiotoxicity observed in this experimental setup.