Anthracyclines in the treatment of cancer. An overview

Anthracyclines are widely used and effective antineoplastic drugs. Although active against a wide variety of solid tumours and haematological malignancies, their clinical use is hindered by tumour resistance and toxicity to healthy tissue. Modification of the general anthracycline ring structure results in analogues with different but overlapping antitumour and tolerability profiles. Activity of the anthracyclines is related to topoisomerase II inhibition, which occurs as a result of anthracycline intercalation between adjacent DNA base pairs. Production of hydroxyl free radicals is associated with antitumour effects and toxicity to healthy tissues. Myocardial tissue is particularly susceptible to free radical damage. Development of tumour cell resistance to anthracyclines involves a number of mechanisms, including P-glycoprotein-mediated resistance. The classical dose-limiting adverse effects of this class of drugs are acute myelosuppression and cumulative dose-related cardiotoxicity. Anthracycline-induced cardiomyopathy is often irreversible and may lead to clinical congestive heart failure. Other toxicities of the anthracyclines, including stomatitis, nausea and vomiting, alopecia and 'radiation recall' reactions, are generally reversible. Anthracycline-induced cardiotoxicity may be reduced or prevented by an administration schedule that produces low peak plasma drug concentrations. Administration of dexrazoxane also provides cardioprotection. Dose intensification of anthracyclines may partly overcome resistance but is associated with reduced tolerability. Liposomal encapsulation of doxorubicin or daunorubicin alters the pharmacokinetic properties of the drugs. Increased distribution in tumours, prolonged circulation and reduced free drug concentrations in plasma may increase antitumour activity and improve the tolerability of the anthracyclines.