Stimulation of the topoisomerase II induced DNA cleavage sites in the c-myc protooncogene by antitumor drugs is associated with gene expression

Abstract

The antitumor drugs mAMSA and VM26 were shown to stimulate the topoisomerase II (Topo II) cleavage activity on the c-myc protooncogene in several human tumor cell lines (N417, HL60, EJ, H146, CaSki, A431, IGROV1, and CAL18A) and human peripheral lymphocytes. The mAMSA-induced gene cleavage was found to increase with the steady-state levels of c-myc transcripts in cell lines while no cleavage could be evidenced in the other genes so far tested. In mAMSA-treated N417 cells, the overall genomic DNA cleavage detected by alkaline elution was found to be about 20 times lower than the c-myc gene cleavage. Topo II mRNA levels were associated with the nuclear Topo II decatenating activity in cell lines and increased with c-myc cleavage. Topo II decatenating activity was found to be 3 times lower in quiescent than in exponentially growing N417 cells, but the c-myc cleavage induced by mAMSA was found as intense in quiescent as in growing cells. Thus, our data seem to indicate that c-myc gene cleavage is not related to cellular Topo II content but rather to c-myc gene transcription. Therefore, we suggest that only a small fraction of the Topo II is able to react with drug on the c-myc gene in relation to its transcriptional accessibility. Since c-myc overexpression is frequently found to be related to human cancer progression, we suggest that this gene could be an important target for Topo II related antitumor drugs.