The Role of Free Radical Damage in the Genesis of Doxorubicin Cardiac Toxicity

Abstract

Between 1975 and 1977, Sato and coworkers (1–3) published a series of papers that documented the conversion of daunorubicin and doxorubicin to semiquinone radicals by the microsomal enzyme P450 reductase. In addition, these workers showed that these semiquinone radicals could, in turn, reduce oxygen to superoxide radicals. In 1977, we put forth the hypothesis that the cardiac toxicity of these agents might be the result of oxygen-radical generation in cardiac tissue (4). In that same year, Thayer (5) showed that doxorubicin stimulated superoxide production fran submitochondrial particles from cardiac mitochondria, and Bachur (6) showed oxygen-radical production fran cardiac sarcosomes. In the years that have followed, these observations have been extended and the free radical hypothesis now stands as the one that most nearly accounts for the characteristics of this cardiamyopathy. The chemistry of anthracycline free radicals will be discussed in other chapters of this book. Briefly, however, the semiquinone radicals will react rapidly with oxygen to yield superoxide radicals. When oxygen availability is limited, these radicals can undergo a rearrangement (halftime of 1 second) to an aglycone free radical that appears to be capable of alkylating (7,8) both proteins and DNA. Therefore, in considering tissue damage from anthracycline radicals, one must consider not only the damage caused by superoxide and its reaction products, but also that which results directly from the reactivity of the drug radical.