Pathogenesis and prevention of doxorubicin cardiomyopathy.
A review is presented of the various types of cardiotoxicity associated with the clinical use of doxorubicin, a highly effective antineoplastic agent of the anthracycline family. Acute toxicity is related to rapid intravenous administration of the drug and is manifested by vasodilatation, hypotension and cardiac arrhythmias. Subacute toxicity is very uncommon. It develops early in the course of therapy and is characterized by myocarditis and pericarditis. Chronic toxicity is the most common form of doxorubicin-induced cardiac toxicity. It is manifested by chronic dilated cardiomyopathy, which develops late in the course of therapy or shortly after its termination. Morphologic changes are characteristic and consist of myofibrillar loss and cytoplasmic vacuolization (which is due to dilatation of the sarcoplasmic reticulum) of the myocytes. The damaging effects of reactive oxygen species, generated by the interaction of doxorubicin with iron, play a critically important role in the pathogenesis of the chronic cardiotoxicity. Other factors related to this toxicity include inhibition of DNA topoisomerase II, stimulation of certain immune responses and a diversity of other biochemical effects on various cellular organelles. Doxorubicin induces apoptosis in a variety of cell types, but not in cardiac myocytes. The chronic cardiotoxicity of doxorubicin is significantly attenuated by chelation of iron by ICRF-187 (dexrazoxane). A greatly delayed type of doxorubicin cardiotoxicity has been recently found to occur in survivors of childhood cancers who were treated with doxorubicin without any immediate adverse effects, but develop chronic cardiomyopathy at periods of time ranging up to 15 years later. The pathogenesis of this type of toxicity remains to be determined.
Ferrans
V J
VJ
Pathology Section, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Clark
J R
JR
Zhang
J
J
Yu
Z X
ZX
Herman
E H
EH
D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000145:classification / Q000517:prevention & control*; D002317:Cardiovascular Agents / Q000627:therapeutic use*; D004317:Doxorubicin / Q000009:adverse effects*; D006801:Humans
D000903:Antibiotics, Antineoplastic; D002317:Cardiovascular Agents; D004317:Doxorubicin