Anthracyclines and heart failure.

Since their discovery more than 50 years ago, anthracyclines have become the mainstay for the treatment of many cancers. However, anthracyclines are associated with a risk of heart failure, with the risk proportionate to the cumulative exposure; cardiac injury appears to occur with every dose, and cardiac-biopsy specimens obtained within hours after a single dose of an anthracycline (e.g. doxorubicin or daunorubicin) show pathologic changes.1 Much effort has gone into finding ways to prevent anthracycline cardiotoxicity, yet advanced heart failure remains a consequence of anthracycline exposure. Moreover, symptomatic heart failure often occurs years after cancer treatment, making it difficult to evaluate preventive strategies. The dominant theory of how anthracyclines cause heart damage involves the generation of reactive oxygen species, which results in damage to DNA, proteins, and lipids and leads to cellular dysfunction and myocyte death. However, results from a recent study by Zhang et al.2 suggest that the first step in cardiac myocyte damage from anthracyclines is independent of reactive oxygen species and depends instead on drug interactions with a particular type of topoisomerase, an enzyme that affects the tension and topologic features of DNA. Anthracyclines disrupt tumor growth by binding to and blocking the function of topoisomerase II (TOP2). Topoisomerases break, twist, and reseal the phosphate backbone of DNA and, in so doing, permit a readjustment in the tension of the double helix during replication and transcription. Anthracyclines intercalate into DNA and form complexes with TOP2 that disrupt the activity of the enzyme and activate a DNA-damage response, leading to cell death. There are several forms of topoisomerase. Rapidly dividing tumor cells express high levels of topoisomerase II alpha (TOP2A). TOP2 beta (TOP2B) is ubiquitously expressed; cardiomyocytes express TOP2B but not TOP2A. Anthracyclines target both TOP2A and TOP2B. Anthracyclines are thought to cause cardiomyocyte damage by driving reactions that result in the formation of free radicals, which in turn can react with and disrupt the function of many cellular constituents, causing dysfunction and cell death. Numerous studies in isolated cells and in animals have shown cardioprotective effects of antioxidants, lending support to the hypothesis that, as a consequence of anthracycline exposure, reactive oxygen species wreck cardiomyocytes (Fig. 1). However, clinical trials of antioxidants for the prevention of anthracycline-induced cardiac injury have been disappointing. Nevertheless, dexrazoxane, a compound that chelates iron and prevents hydroxyl radical formation in the presence of anthracyclines, prevents cardiac injury, lending support to the hypothesis regarding reactive oxygen species. (Dexrazoxane has been approved by the Food and Drug Administration for the prevention of anthracycline cardiotoxicity.) On the other hand, some research has challenged the hypothesis regarding reactive oxygen species. Using mouse cells in culture, Lyu et al.3 have shown that anthracycline-induced DNA breaks and cell death in a cardiomyocyte cell line depend on the presence of Top2b. Building on this finding, Zhang et al. genetically engineered mice to lack Top2b specifically in their cardiomyocytes. In contrast with control mice, the mutant mice did not have acute or chronic cardiac injury after exposure to doxorubicin, a commonly used anthracycline. Nor did these mice have reductions in left ventricular ejection fraction, a key characteristic of doxorubicin cardiotoxicity. Zhang et al. observed the formation of reactive oxygen species, consequent to interactions among doxorubicin, Top2b, and DNA in the wildtype mice. The formation of reactive oxygen species appeared to be caused by the disruption of mitochondrial function, rather than a consequence of reduction–oxidation cycling of doxorubicin quinones. Analysis of cardiac tissue from the doxorubicin-treated wild-type mice revealed