In vivo stimulation by antitumor drugs of the topoisomerase II induced cleavage sites in c-myc protooncogene.
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.
D000609:Aminoacridines / Q000494:pharmacology; D000677:Amsacrine; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D002874:Chromosome Mapping; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000235:genetics; D003850:Deoxyribonuclease I; D004611:Ellipticines / Q000494:pharmacology; D005784:Gene Amplification; D005786:Gene Expression Regulation / Q000187:drug effects; D005796:Genes; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology; D009154:Mutation / Q000187:drug effects; D011519:Proto-Oncogenes; D013713:Teniposide / Q000494:pharmacology
D000609:Aminoacridines; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004611:Ellipticines; D007364:Intercalating Agents; D000677:Amsacrine; D013713:Teniposide; C008009:9-hydroxyellipticine; D003850:Deoxyribonuclease I; D004250:DNA Topoisomerases, Type II