Suppression of c-myc oncogene expression by a polyamine-complexed triplex forming oligonucleotide in MCF-7 breast cancer cells.
Suppression of c-myc oncogene expression by a polyamine-complexed triplex forming oligonucleotide in MCF-7 breast cancer cells.
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DOI：
10.1093/nar/23.17.3594
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发表时间：
1995-09
影响因子：
14.9
通讯作者：
Thekkumkat Thomas;C. Faaland;Michael A. Gallo;Thresla Thomas
中科院分区：
文献类型：
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作者：
Thekkumkat Thomas;C. Faaland;Michael A. Gallo;Thresla Thomas
多胺是三链体 DNA 的优良稳定剂。我们实验室最近的研究揭示了多胺在三链 DNA 的诱导和稳定方面具有显着的结构特异性。在一系列合成二胺中，1,3-二氨基丙烷 (DAP) 在稳定三链体 DNA 方面表现出最佳功效。为了利用这一发现开发乳腺癌抗基因策略的潜力，我们用 37mer 寡核苷酸处理 MCF-7 细胞，在 DAP 存在的情况下在 c-myc 癌基因的上游调控区域形成三链体 DNA。作为单独的药物，寡核苷酸和 DAP 在雌二醇存在的情况下不会下调 c-myc mRNA。寡核苷酸与 2 mM DAP 复合，在 10 microM 寡核苷酸浓度下，c-myc mRNA 信号降低了 65%。相反，对照寡核苷酸对c-myc mRNA没有显着影响。 c-fos癌基因的表达没有被三链体形成寡核苷酸(TFO)显着改变。 DAP在治疗后1小时内内化；然而，它对天然多胺的水平没有显着影响。这些数据表明，选择性利用合成多胺和 TFO 可能是开发基于抗基因的乳腺癌治疗方式的重要策略。
Polyamines are excellent stabilizers of triplex DNA. Recent studies in our laboratory revealed a remarkable structural specificity of polyamines in the induction and stabilization of triplex DNA. 1,3-Diaminopropane (DAP) showed optimum efficacy amongst a series of synthetic diamines in stabilizing triplex DNA. To utilize the potential of this finding in developing an anti-gene strategy for breast cancer, we treated MCF-7 cells with a 37mer oligonucleotide to form triplex DNA in the up-stream regulatory region of the c-myc oncogene in the presence of DAP. As individual agents, the oligonucleotide and DAP did not downregulate c-myc mRNA in the presence of estradiol. Complexation of the oligonucleotide with 2 mM DAP reduced c-myc mRNA signal by 65% at 10 microM oligonucleotide concentration. In contrast, a control oligonucleotide had no significant effect on c-myc mRNA. The expression of c-fos oncogene was not significantly altered by the triplex forming oligonucleotide (TFO). DAP was internalized within 1 h of treatment; however, it had no significant effect on the level of natural polyamines. These data indicate that selective utilization of synthetic polyamines and TFOs might be an important strategy to develop anti-gene-based therapeutic modalities for breast cancer.