Anthracyclines in haematology: preclinical studies, toxicity and delivery systems

The anthracyclines are widely used in the treatment of haematological and non-haematological malignancy and there is now more than 30 yearsʹ clinical experience with these agents but despite this, their mechanism of action is incompletely understood. The anthracyclines have been shown to intercalate with DNA and indirectly inhibit the activity of the enzyme topoisomerase 11, resulting in DNA strand breaks. More recently, workers have focused on induction of apoptosis and have shown that daunorubicin stimulates production of the apoptotic mediator, ceramide and that the activity of doxorubicin can be blocked by inhibitors of CD95 (fas). One of the major problems with anthracycline therapy is the development of resistance which may be mediated by p-glycoprotein or by other mechanisms. Much recent research has concentrated on methods to modulate the drug-resistant phenotype and these include development of new analogues and use of specific reversal agents. The toxicity profile of the anthracyclines includes bone marrow suppression, severe local reaction following extravasation, radiation recall, alopecia, gastrointestinal and hepatic effects, development of secondary malignancies and significant cardiac toxicity. The risk factors for the development of anthracycline-related cardiac toxicity are well documented and several methods have been exploited in attempts at prevention. Finally, a number of drug delivery systems have been developed in order to improve therapeutic response and reduce toxicity to normal tissues, including the use of liposomal preparations.