Topoisomerase II enzymes and mutagenicity.
Topoisomerase II (topo II) enzymes maintain DNA structure by relieving torsional stress occurring in double-strand DNA during transcription and replication. Topo II causes transient breaks in both strands of DNA, allowing passage of one double helix through another, and probably acts as a structural protein in interphase cells, playing a role in the organisation of mitotic and meiotic chromosomes. A number of clinical anticancer drugs are thought to act on topo II enzymes to stabilise DNA-drug-topo II ternary complexes known as "cleavable complexes." These complexes may lead to illegitimate recombination events, as well as to the formation of other DNA lesions. Topo II-mediated genotoxicity is strongly dependent on the cell cycle status of the target cells. It is now apparent that some dietary components and environmental chemicals may act on topo II. Since the structural features of chemicals that lead to topo II interaction are not clear, it is currently not possible to predict such activity from chemical structure. For many years, the central dogma of chemical carcinogenesis has been that the most carcinogenic chemicals are those that can form a covalent bond with DNA, either directly or after metabolic activation. Topo II-directed drugs are not usually capable of forming covalent bonds with DNA and tend to have low mutagenicity in microbial assays. However, topo II-directed agents are potent cancerogens, inducing characteristic cytogenetic modifications. It is important to define the most sensitive tests to identify topo II-directed mutagens and to develop appropriate strategies for genotoxicity testing of such chemicals.
Ferguson
L R
LR
Cancer Research Laboratory, University of Auckland Medical School, New Zealand.
Baguley
B C
BC
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects / Q000235:genetics; D004250:DNA Topoisomerases, Type II / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008540:Meiosis / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects; D016296:Mutagenesis / Q000187:drug effects / Q000235:genetics; D009152:Mutagenicity Tests; D013045:Species Specificity; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
D000970:Antineoplastic Agents; D002273:Carcinogens; D004250:DNA Topoisomerases, Type II