title: Topoisomerase II Inhibitors and Poisons, and the Influence of Cell Cycle Checkpoints.
abstract: Interactions between the decatenation checkpoint and Topoisomerase II (TopoII) are vital for maintaining integrity of the genome. Agents that target this enzyme have been in clinical use in cancer therapy for over 30 years with great success. The types of compounds that have been developed to target TopoII are broadly divided into poisons and catalytic inhibitors. The TopoII poisons are in clinical use as anti-cancer therapies, although in common to most chemotherapeutic agents, they display considerable normal tissue toxicity. Inhibition of the TopoIIb isoform has been implicated in this cytotoxicity. Response to TopoII active agents is determined by several factors, but cell cycle checkpoints play a large role in sensitivity and resistance. The G2/M phase checkpoints are of particular importance in considering the effectiveness of these drugs and are reviewed in this article. Functionality of the ATM dependent decatenation checkpoint may represent a new avenue for selective cancer therapy. Here we review the function of TopoII, the anti-cancer mechanisms and limitations of current catalytic inhibitors and poisons, and their influence on cell cycle checkpoints. We will also assess potential new mechanisms for targeting this enzyme to limit normal tissue toxicity, and how the cell cycle checkpoint triggered by these drugs may provide an alternative and possibly better target for novel therapies.
authors.affiliation: Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane 4102 Queensland. Australia.
authors.forename: Nicholas
authors.initials: N
authors.lastname: D Arcy
authors.affiliation: Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane 4102 Queensland. Australia.
authors.forename: Brian
authors.initials: B
authors.lastname: Gabrielli
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D000071877:Checkpoint Kinase 1 / Q000378:metabolism; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D059005:Topoisomerase II Inhibitors; D016159:Tumor Suppressor Protein p53; D064447:Checkpoint Kinase 2; D064007:Ataxia Telangiectasia Mutated Proteins; D000071877:Checkpoint Kinase 1; D004250:DNA Topoisomerases, Type II
keywords: G2/M phase checkpoints; TopoII poison; Topoisomerase II; cell cycle checkpoints; cytotoxicity; genome integrity