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Acute anthracycline cardiotoxicity. Comparative morphologic study of three analogues
Abstract:
Chemotherapeutic use of anthracycline antibiotics is limited by their cardiotoxic effects. A potential solution to this problem is the development of anthracycline analogues retaining antitumor efficacy but without cardiac toxicity. An isolated perfused rabbit heart model was used to compare the nature and extent of early ultrastructural effects on the myocyte of three anthracycline analogues purported to have lesser cardiotoxicity than Adriamycin (doxorubicin). Seventeen rabbit hearts were perfused with oxygenated Krebs-Ringer bicarbonate buffer at 39 degrees C containing either Adriamycin (4 mg/L), daunomycin (10.6 mg/L), aclacinomycin (8 mg/L), or rubidazone (17.6 mg/L). For comparison, three hearts each were exposed to phosphoramide mustard (14.7 mg or 25 mg/L) or 4-hydroperoxy cyclophosphamide (24 mg or 17 mg/L), two active congeners of cyclophosphamide, an agent interacting with DNA differently than the anthracyclines and which is known to be cardiotoxic in high dose. Two hearts were exposed to dactinomycin (0.1 mg or 0.2 mg/L) which intercalates with DNA in a manner similar to the anthracyclines but which is not cardiotoxic. Ten control hearts were perfused with oxygenated buffer solution only. Light microscopic study disclosed no differences between treated and control hearts. Electron microscopic examination showed a striking and distinctive clumping of nuclear chromatin with clearing of chromatin from the nuclear membrane in all anthracycline treated hearts but in no hearts treated with 4-hydroperoxy cyclophosphamide, phosphoramide Mustard, dactinomycin, or control hearts. The nuclear effects of the four anthracycline analogues were indistinguishable. Thus, all anthracycline analogues studied produced acute nuclear alterations which were distinctive from the changes produced by other DNA interactive chemotherapeutic agents. The relationship of the distinctive anthracycline nuclear changes to the late cardiomyopathy requires further definition.
Insights
Anthracycline chemotherapy drugs cause heart damage. New analogues showed similar nuclear changes in rabbit hearts, suggesting potential for reduced cardiotoxicity while maintaining anti-cancer effects.
Area of Science:
- Cardiovascular Toxicology
- Cancer Chemotherapy
- Pharmacology
Background:
- Anthracycline antibiotics are effective chemotherapeutics but their use is limited by dose-dependent cardiotoxicity.
- Developing anthracycline analogues with reduced cardiac toxicity is a critical goal in cancer treatment.
Purpose of the Study:
- To compare the early ultrastructural effects of Adriamycin (doxorubicin) and three purported less cardiotoxic anthracycline analogues on rabbit myocytes.
- To investigate if these analogues induce distinctive nuclear alterations compared to other DNA-interactive agents.
Main Methods:
- Isolated perfused rabbit heart model.
- Perfusion with Adriamycin, daunomycin, aclacinomycin, rubidazone, cyclophosphamide congeners (phosphoramide mustard, 4-hydroperoxy cyclophosphamide), or dactinomycin.
- Electron microscopic examination of myocyte ultrastructure.
Main Results:
- All four anthracyclines induced a distinctive clumping of nuclear chromatin.
- No such nuclear changes were observed with cyclophosphamide congeners or dactinomycin.
- The nuclear alterations caused by the anthracycline analogues were indistinguishable from each other.
Conclusions:
- The studied anthracycline analogues produce acute, distinctive nuclear alterations in myocytes.
- These nuclear changes are unique compared to other DNA-interactive chemotherapeutic agents.
- Further research is needed to correlate these early nuclear changes with late-onset cardiotoxicity.