Topoisomerase I inhibitors: camptothecins and beyond

Nuclear DNA topoisomerase I (TOP1) is an essential human enzyme, and is the only known target of the camptothecin and its derivatives. The mechanisms and molecular determinants of the tumour response to TOP1 inhibitors are reviewed in the context of developing camptothecin and non-camptothecin derivatives that further increase anti-tumour activity but also reduce side effects. 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.