Mechanism of action of eukaryotic DNA topoisomerase I and drugs targeted to the enzyme.
DNA topoisomerase I is essential for cellular metabolism and survival. It is also the target of a novel class of anticancer drugs active against previously refractory solid tumors, the camptothecins. The present review describes the topoisomerase I catalytic mechanisms with particular emphasis on the cleavage complex that represents the enzyme's catalytic intermediate and the site of action for camptothecins. Roles of topoisomerase I in DNA replication, transcription and recombination are also reviewed. Because of the importance of topoisomerase I as a chemotherapeutic target, we review the mechanisms of action of camptothecins and the other topoisomerase I inhibitors identified to date.
Pommier
Y
Y
Laboratory of Molecular Pharmacology, Division of Basic Sciences, National Cancer Institute, Bethesda, MD 20892-4255, USA. pommier@nih.gov
Pourquier
P
P
Fan
Y
Y
Strumberg
D
D
D000970:Antineoplastic Agents / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology* / Q000627:therapeutic use; D004247:DNA / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000502:physiology*; D004351:Drug Resistance / Q000235:genetics; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D011083:Polycyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007364:Intercalating Agents; D011083:Polycyclic Compounds; D059004:Topoisomerase I Inhibitors; D004247:DNA; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin