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Mechanisms of Topoisomerase I Inhibition by Anticancer Drugs

1994; Elsevier BV; Linguagem: Inglês

10.1016/s1054-3589(08)61132-1

1557-8925

Yves Pommier, Akihiko Tanizawa, Kurt W. Kohn,

Neutropenia and Cancer Infections

DNA topoisomerase I (top1) prevents the accumulation of DNA torsional tension, and its activity is essential for DNA replication, RNA transcription, and also for DNA repair and genetic rearrangements. So top1 has become an important target for cancer chemotherapy. Top1 is concentrated in the nucleolus. This chapter discusses topoisomerase I reaction mechanisms, inducers and suppressors of top1-linked DNA breaks, camptothecins and other drugs that trap top1 cleavable complexes. Top1 is a phosphoprotein. Its function is to reduce the torsional stress of DNA supercoiling by altering the number of twists of one DNA strand about the other. At low salt concentration, this action is processive in that the enzyme remains bound to the same DNA molecule while progressively changing the linking number; thus, the torsional stress becomes completely relaxed in some molecules before others have begun the process, few molecules being in intermediate states at any given time during the course of the reaction. Addition of Mg2+ increases the relaxation rate. Top1-DNA binding can occur at many base sequenes, and is most efficient in some regions of bent or supercoiled DNA. Top1 also binds to DNA nicks in duplex DNA and cleaves the intact DNA strand opposite the nick. The local DNA base sequence around top1 sites influences cleavage induction. The chapter discusses inhibition of top1-mediated DNA relaxation, camptothecin-induced DNA damage in cells, mechanism of camptothecin cytotoxicity, and camptothecin derivatives selected for trials. DNA replication inhibition is partially reversible after camptothecin removal, while top1-induced DNA breaks reverse quickly. Camptothecin cytotoxicity is dependent on the exposure of cells to the drug.