Abstract

Recent years have seen the development of the latest generation of inhibitors of the topoisomerase enzymes. New discoveries and improvements to methodologies underpinning drug design and discovery have caused a renewed interest in the ubiquitously expressed DNA topoisomerases. Virtually every aspect of nucleic acid physiology is influenced by the topological state of DNA, which is managed predominantly by these enzymes. For this reason, they have been the targets of clinically important anti-cancer drugs for a number of years. Although the emergence of targeted therapies may have diminished the interest in topoisomerases, clinically established drugs such as irinotecan and etoposide will remain the mainstay treatment of cancer both as single agents and more recently, in combinatorial programs. By todays standards, these first generation inhibitors are crude, and their applications limited by non-ideal drug characteristics. However, the new inhibitors, such as diflomotecan, gimatecan, ICRF-193 and XR5000 offer enhanced activity through increased metabolic stability and improvements in pharmacokinetic and pharmacodynamic profiles. These developments have resulted in improved drug delivery and in reductions in adverse effects. This review will revisit this class of anti-cancer agent, and will summarise and update the exciting developments in the field.

Keywords: Topoisomerase, topoisomerase inhibitors, camptothecin, etoposide, combination, cytotoxic agents