Doxorubicin and mechanical performance of cardiac trabeculae after acute and chronic treatment: a review

Doxorubicin, a very potent and often used anti-cancer drug, has a wide spec trum of biological activity. Classic studies have demonstrated that doxorub icin and other members of the anthracycline family intercalate with DNA and partially uncoil the double-stranded helix. Doxorubicin has a high affinit y for cell nuclei: as much as 60% of the total intracellular amount of doxo rubicin is found in the nucleus. Once binding to DNA occurs, several conseq uences may ensue. The binding of anthracyclines to DNA inhibits DNA polymer ase and nucleic acid synthesis. In addition, anthracyclines are known to st abilize the otherwise cleavable complex between DNA and homodimeric topoiso merase II enzyme subunits, resulting in the formation of protein-linked DNA double strand breaks. In tumor cells, these anthracycline-induced perturba tions are believed to result in a final common pathway of endonucleolytic D NA fragmentation known as apoptosis. Because proliferation is an important determinant of tumor growth, interference with the genome is regarded as th e primary cause of the anti-tumor action of doxorubicin. Intercalation with DNA may not be important in the cardiotoxicity associated with doxorubicin therapy (see next section), because cardiac cell proliferation in humans s tops after 2 months of age. This review is focussed on the effects of doxor ubicin on mechanical performance in skinned cardiac trabeculae after acute and chronic administration of doxorubicin. We look especially at the mechan ical performance and the molecular changes observed and related to mechanic al performance. (C) 2001 Elsevier Science B.V. All rights reserved.