publication . Article . 2006

Topoisomerase I inhibitors: camptothecins and beyond

Pommier, Yves;
Open Access
  • Published: 01 Oct 2006
  • Publisher: Springer Science and Business Media LLC
Abstract
Topoisomerase I (TOP1) enzymes are essential in higher eukaryotes, as they are required to relax DNA supercoiling generated by transcription, replication and chromatin remodelling. Topoisomerases are particularly vulnerable to topoisomerase I inhibitors during their cleavage reaction, which is referred to as the 'cleavage complex'. TOP1 can be trapped by anticancer drugs as it cleaves DNA. Moreover, TOP1 can be trapped by endogenous alterations to DNA (mismatches, abasic sites, nicks and adducts) and apoptotic alterations to chromatin. Camptothecin is a natural product of which TOP1 is the only cellular target. Two camptothecin derivatives have recently been approved by the US Food and Drug Administration: topotecan for ovarian and lung cancers and irinotecan for colorectal cancer. Various non-camptothecin inhibitors of TOP1 are in development, including indolocarbazole, phenanthridine and indenoisoquinoline derivatives. Non-camptothecins are expected to be active in cancers that are currently resistant to camptothecins, and to have a greater therapeutic index. Co-crystal structures of TOP1 inhibitors illustrate the interfacial inhibition paradigm by which a small drug molecule can trap conformational intermediates of macromolecular complexes (in the case of TOP1 inhibitors, the TOP1 enzyme and its cleaved DNA substrate). The cytotoxic activity of TOP1 inhibitors is related to the interference of trapped TOP1 cleavage complexes with DNA replication and transcription. Deficiencies in both the checkpoint and DNA-repair pathways determine cellular sensitivity to TOP1 inhibitors. Therefore, the identification of such deficiencies in tumours should guide the rational use of TOP1 inhibitors. Targeting checkpoint and repair pathways should also increase the selectivity of TOP1 inhibitors in tumours that have pre-existing deficiencies in relevant redundant pathways.
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free text keywords: Biology, Topoisomerase-I Inhibitor, Topoisomerase, biology.protein, Camptothecin, medicine.drug, medicine, Biochemistry, TDP1, DNA damage, Topotecan, Irinotecan, DNA repair
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