Recent developments in the clinical activity of topoisomerase-1 inhibitors

Topoisomerase-1 is a key sub-cellular target for anti-cancer therapy. This intranuclear enzyme, responsible for DNA replication and repair, undergoes interaction with camptothecin and several semi-synthetic camptothecin analogs to produce cell-death. Preclinical studies on the mechanism of action and metabolism of these drugs are reviewed. Clinical activity including phases I–III studies is reviewed for topotecan (FDA approved for the indications of ovarian and small-cell lung cancers) and irinotecan (approved for colon cancer and non-small-cell lung cancer). Activity in numerous other settings is reviewed for these approved agents. Other topoisomerase-1 inhibitors currently being tested in the clinic including 9-amino and 9-nitro camptothecin, exatecan, lurtotecan and edotecarin are reviewed for both preclinical rationale and clinical trials. Topoisomerase-1 inhibition is a validated approach to cancer treatment and remains an area of active drug development.