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.
Nuclear DNA topoisomerase I (TOP1) is an essential human enzyme. It is the only known target of the alkaloid camptothecin, from which the potent anticancer agents irinotecan and topotecan are derived. As camptothecins bind at the interface of the TOP1–DNA complex, they represent a paradigm for interfacial inhibitors that reversibly trap macromolecular complexes. Several camptothecin and non-camptothecin derivatives are being developed to further increase anti-tumour activity and reduce side effects. The mechanisms and molecular determinants of tumour response to TOP1 inhibitors are reviewed, and rational combinations of TOP1 inhibitors with other drugs are considered based on current knowledge of repair and checkpoint pathways that are associated with TOP1-mediated DNA damage.
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I wish to thank K. W. Kohn for many years of enjoyable collaboration and inspiration, as well as all current and past members of the Laboratory of Molecular Pharmacology. Special thanks to O. Sordet and Z. Miao for their careful reading of the manuscript and suggestions. This research was supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research.
The author declares no competing financial interests.
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Topoisomerases are divided into type I and II. Type I enzymes cleave only one strand of duplex DNA whereas type II enzymes cleave both strands. Type I topoisomerases are further subdivided into type IA and IB. Type IA enzymes cleave the DNA by forming a 5′-phosphotyrosyl covalent bond and relax DNA supercoiling by a strand-passing mechanism, whereas type IB enzymes form a covalent bond with the 3′ end of the DNA, and relax DNA by controlled rotation.
- DNA supercoiling
In relaxed normal B-DNA, each strand crosses the other once every 10.4 base pairs with a right-handed turn. DNA is negatively supercoiled ('underwound') when the strands cross each other at more than a 10.4 base-pair interval. DNA is positively supercoiled ('overwound') when the strands cross each other with a base-pair interval less than 10.4.
- Nucleophilic attack
A nucleophile is a chemical compound or group that is attracted to nuclei (centres of positive charge) and tends to donate or share electrons. A nucleophilic chemical reaction consists of the donation of electrons from a nucleophile to another species known as an electrophile in order to form a chemical bond. Nucleophiles can take part in nucleophilic substitution, whereby a nucleophile becomes attracted to a full or partial positive charge on an element and displaces the group to which it is bonded.
- Chiral centre
From the Greek word cheir (which translates as 'hand' in English) to mean objects that have non-superimposable mirror images. It is synonymous with stereocentre (for instance an asymmetric carbon atom) whose spatial structure determines whether the enantiomer is in the R configuration (from the Latin 'rectus': right) or the S configuration (from the Latin 'sinister': left).
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Pommier, Y. Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer 6, 789–802 (2006). https://doi.org/10.1038/nrc1977
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