Stimulation of the topoisomerase II induced DNA cleavage sites in the c-myc protooncogene by antitumor drugs is associated with gene expression.
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.
Riou
J F
JF
Laboratoire de Pharmacologie Clinique et Moléculaire, Institut Gustave Roussy, Villejuif, France.
Lefevre
D
D
Riou
G
G
D000677:Amsacrine / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D011519:Proto-Oncogenes; D012333:RNA, Messenger / Q000378:metabolism; D013713:Teniposide / Q000494:pharmacology; D014349:Trypanosoma cruzi; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D000677:Amsacrine; D004247:DNA; D013713:Teniposide; D004250:DNA Topoisomerases, Type II