In vivo stimulation by antitumor drugs of the topoisomerase II induced cleavage sites in c-myc protooncogene |
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Authors: | J F Riou E Multon M J Vilarem C J Larsen G Riou |
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Institution: | 1. Institute of Science and Technology for Ceramics-National Research Council (ISTEC-CNR), Faenza, Italy;2. RISE-PFI, Trondheim, Norway;3. Department of Clinical Dentistry, University of Bergen, Bergen, Norway;4. BioNanoMetals Group, Department of Inorganic Chemistry, Facultad de Ciencias, Universidad de Granada, Granada;5. Department of Chemical Engineering, Norwegian University of Science and Technology, Trondheim, Norway |
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Abstract: | Several antitumor drugs including DNA intercalative and non intercalative agents induce in vitro and in vivo double-stranded DNA breaks by stabilization of a topoisomerase II-DNA complex. In order to locate cleavage sites in an actively transcribed oncogene, N417 cells, originating from a human small cell lung carcinoma and containing 45-50 copies of c-myc oncogene, were treated with mAMSA, 9 hydroxyellipticine and VM 26. The presence of DNA lesions in c-myc was investigated by Southern blot hybridization with a human c-myc probe. In addition to normal bands, DNA patterns of drug treated-cells revealed the presence of new bands most likely corresponding to topoisomerase II-mediated cleavage as these bands were not found in untreated control DNA and in DNA treated with oAMSA, a biologically inactive stereoisomer of mAMSA. Major cleavage sites induced by drugs in the N417 cell c-myc locus were located in the 5' end of the c-myc exon 1 closely to some DNAse I hypersensitive sites which are assumed to reflect an activity of the gene. Therefore our data suggest that TopoII-mediated drug activity correlates with gene activity. |
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