In situ stimulation of topoisomerase II-induced cleavage sites in the c-myc protooncogene by antitumor agent pMC540 is associated with gene expression.
The antitumor activity of pMC540 has been shown to be mediated via its interaction with topoisomerase (Topo) II eventually leading cells into apoptosis. This agent was also found to down regulate the expression of the c-myc oncogene in L1210 leukemia cells. To investigate the possibility that damage within select genomic regions may contribute to the antiproliferative activity of pMC540, differential damage in regions surrounding the c-myc locus as well as other select genes was determined. Southern blot hybridization experiments show that pMC540 treatment induces in situ DNA cleavage products in the 5' end of the c-myc oncogene of L1210 leukemia cells. In cells pre-treated with 50 microM ethidium bromide, an inhibitor of the Topo II-dependent DNA cleavage, a subsequent treatment with pMC540 failed to induce DNA cleavage, suggesting that the cleavage activity of pMC540 was Topo II dependent. pMC540-induced cleavage does not appear to correlate with the over-expression of the c-myc oncogene in these cells as another over-expressed gene c-myb was not affected. Thus, it is proposed that the c-myc gene may be a preferred target for pMC540 may mediated antiproliferative activity.
Sharma
R
R
Baylor University Medical Center, Baylor Research Institute, Dallas, TX 75226, USA.
Gulliya
K S
KS
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015139:Blotting, Southern; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004996:Ethidium; D016259:Genes, myc / Q000187:drug effects*; D051379:Mice; D011744:Pyrimidinones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D011744:Pyrimidinones; C003954:merocyanine dye; D004250:DNA Topoisomerases, Type II; D004996:Ethidium