Eukaryotic DNA topoisomerase I: genome gatekeeper and its intruders, camptothecins

Topoisomerase I enzymes are ubiquitous and play a pivotal role in DNA transcription, replication, and repair. The eukaryotic form of this enzyme is highly conserved and its inhibition leads to accumulation of DNA strand breaks ('cleavable complexes') and ultimately cell death. An understanding of the role of eukaryotic topoisomerase I has led researchers to identify this enzyme as a potential target for anticancer therapy. Indeed, topoisomerase I is inhibited by samptothecin (isolated from a plant extract), and derivatives of this agent are being developed with improved physicochemical and pharmacologic characteristics. These agents may provide a new dimension to chemotherapy through their novel mechanism of action.