[Molecular mechanisms of anthracyclines action]

Abstract

Anthracyclines have been in use for almost 40 years for the treatment of many malignancies. During this period, hundreds of analogs of the first two anthracycline antibiotics, doxorubicin and daunorubicine, have been synthesized and evaluated. Multiple mechanisms have been proposed to explain the cytostatic and cytotoxic actions of anthracyclines. These include free radical formation, lipid peroxidation, and direct membrane effects. The best characterized, however, are interactions with the DNA-topoisomerase II complex or DNA itself via intercalation or covalent binding formation and base modification, which in turn are responsible for disturbances in DNA replication and transcription, and then the induction of DNA repair or apoptotic cell death. There is evidence that at low concentrations, anthracyclines can induce a differentiation program in proliferating cells. The search for the relationship between the structure of anthracyclines and their mode of action in vitro or their clinical effectiveness is continuing. The concentrations of the drugs is important in these studies since not all the mechanisms of action observed in vitro seem to be responsible for clinical effects and, on the other hand, the drug action associated with their clinical utilization is very complex. Because of anthracycline-induced cardiotoxicity, an important part of the research is focused on new methods of drug delivery to cancer cells. We review recent progress in understanding the molecular mechanisms of anthracycline action and the new approaches which are being undertaken to improve their therapeutic index.