NOVEL SEMISYNTHETIC DOXORUBICINS WITH REDUCED CARDIOTOXICITY

Doxorubicin (DOXO) iis a potent broad-spectrum antineoplastic antibiotic belonging to the anthracycline family. It is widely used, as single agent or in combination with other anticancer drugs, in treating a variety of cancers including solid tumors, soft-tissue sarcomas, lymphomas, and leukemias. DOXO displays a number of clinical toxicities, of which cardiomyopathy is the most important. Two kinds of cardiomyopathies can occur: an acute form and a chronic, cumulative dose-related form. The former kind is rarely a serious problem, while the latter can lead to congestive heart failure that is unresponsive to digitalis. The mortality rate in patients with congestive heart failure is close to 50%. The classic molecular mechanisms underlying both the anticancer and the toxic effects of DOXO operate at two distinct levels: by modifying DNA, and by inducing oxidative stress. The heart is very sensitive to oxidative stress, because of its strongly oxidative metabolism and poor antioxidant defenses. DOXO can generate free radicals in a number of different ways: it is reduced by various biological systems to a semiquinone free radical giving rise to a number of ROS, including peroxide anion, hydrogen peroxide, and hydroxyl radical. It is known that the heart is very rich in mitochondria, which contain a phospholipid called cardiolipin, for which DOXO displays great affinity; in consequence, DOXO accumulates in the mitochondria, with production of high levels of ROS. The final result is the cardiomyocyte damage, mainly deriving from the impairment of mitochondrial functioning. The use of the variety of natural and synthetic antioxidants to prevent DOXO induced cardiotoxicity has been considered, and combinations of DOXO with agent(s) capable of blocking its ROS-mediated cardiotoxicity effect have been investigated. As a development of our studies on semi-synthetic doxorubicin, we here report preliminary results obtained with DOXO hybrids, in which the antibiotic is linked with selected antioxidant moieties through appropriate spacers.