What's new in doxorubicin-induced cardiotoxicity

摘要

Doxorubicin (Adriamycin~(R)) is one of the most commonly used and effective anti-neoplastic drugs used in veterinary oncology for a variety of hematological cancers and solid tumors. Despite its efficacy, its use is often limited because of dose-dependent cardiotoxicity. This talk briefly reviews doxorubicin-induced cardiotoxicity and discusses strategies for clinical monitoring and prevention of myocardial injury. The exact mechanism of doxorubicin-induced cardiotoxicity remains elusive, but the most thoroughly studied mechanism is the free radical hypothesis. Free radical generation may occur as a result of the transfer of electrons when the quinone form of doxorubicin is reduced to the free radical semiquinone form by cytochrome P-450 reductaseand flavin-centered reductases. The semiquinone free radical is oxidized rapidly with oxygen to its original quinone form, creating superoxide anions. These superoxide radicals can cause lipid peroxidation; however they are preferentially converted backto oxygen, forming H_2O_2 through superoxide dismutase. The heart's vulnerability to doxorubicin is perhaps best described by its apparent deficiency in enzymatic defenses against free radicals. Mammalian cells detoxify oxygen radicals through superoxide dismutase, catalase and glutathione peroxidase. However, the heart's superoxide dismutase and catalase activity is only 25-30 percent and 1-2 percent of that in the liver, respectively. These free radicals cause severe lipid peroxidation, leading to mitochondrial destruction and efflux of calcium into the cytoplasm. Light and electron microscopic findings include multi-focal myofibrillar degeneration, myocyte vacuolization, and swelling of the sarcoplasmic reticulum and mitochondria. These changes lead to myocardial failure, arrhythmias, conduction disturbances and congestive heart failure.