The localization of topoisomerase II cleavage sites on DNA in the presence of antitumor drugs.
Type II topoisomerase are enzymes that break and religate DNA phosphodiester bonds while crossing over DNA strands and altering DNA topology. They also are structural proteins that play a role in the spatial organization of chromatin and are involved in several crucial biological functions, such as DNA replication and transcription, chromosome segregation and recombination. Many drugs interfere with type II topoisomerases and can be assigned to two groups. Coumarin derivatives and synthetic quinolones act at the level of ATP binding or hydrolysis and are used for controlling bacterial infections. Drugs belonging to the second group produce DNA lesions by trapping a "cleavable complex" consisting of the normal transient topoisomerase II-DNA reaction intermediate in which the enzyme and the DNA are joined by two covalent bonds. There are four main categories of antitumour drugs that form cleavable complexes in eukaryotes: acridines, anthracyclines, ellipticines and epipodophyllotoxins. These drugs are cytotoxic and many--but not all--are endowed with antitumoral properties. The mechanisms of this pharmacological activity are not understood. Topoisomerase II-induced DNA breaks generated from cleavable complexes display different levels of cytotoxicity depending on their localization on DNA. The primary structure of DNA is not the only parameter that determines this localization. The spatial organization of the enzyme-DNA complex and both the topology and the structure of the underlying chromatin fiber constitute additional critical factors. It, therefore, may be unrealistic to expect that the actual pharmacological potency of antitumor drugs that act on type II topoisomerases can be accurately predicted solely on the basis of simple in vitro test tube experiments carried out using pure enzymes and naked DNA.
Institut Gustave Roussy, Villejuif, France.
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Paoletti
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000145:classification / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects*; D006801:Humans; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D002843:Chromatin; D004273:DNA, Neoplasm; D004250:DNA Topoisomerases, Type II