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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The antiproliferative activity of c-myb and c-myc antisense oligonucleotides in smooth muscle cells is caused by a nonantisense mechanism.
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The antiproliferative activity of c-myb and c-myc antisense oligonucleotides in smooth muscle cells is caused by a nonantisense mechanism.

机译：c-myb和c-myc反义寡核苷酸在平滑肌细胞中的抗增殖活性是由非反义机制引起的。

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摘要

Smooth muscle cell (SMC) proliferation is thought to play a major role in vascular restenosis after angioplasty and is a serious complication of the procedure. Developing antisense (AS) oligonucleotides as therapeutics is attractive because of the potentially high specificity of binding to their targets, and several investigators have reported inhibition of SMC proliferation in vitro and in vivo by using AS strategies. We report here the results of our experiments on vascular SMCs using AS oligonucleotides directed toward c-myb and c-myc. We found that significant inhibition of SMC proliferation occurred with these specific AS sequences but that this inhibition was clearly not via a hybridization-dependent AS mechanism. Rather, inhibition was due to the presence of four contiguous guanosine residues in the oligonucleotide sequence. This was demonstrated in vitro in primary cultures of SMCs and in arteries ex vivo. The ex vivo model developed here provides a rapid and effective system in which to screenpotential oligonucleotide drugs for restenosis. We have further explored the sequence requirements of this non-AS effect and determined that phosphorothioate oligonucleotides containing at least two sets of three or four consecutive guanosine residues inhibit SMC proliferation in vitro and ex vivo. These results suggest that previous AS data obtained using these and similar, contiguous guanosine-containing AS sequences be reevaluated and that there may be an additional class of nucleic acid compounds that have potential as antirestenosis therapeutics.
机译：平滑肌细胞（SMC）增殖被认为在血管成形术后血管再狭窄中起主要作用，并且是该过程的严重并发症。由于将反义（AS）寡核苷酸与靶标结合的潜在高度特异性，因此将其开发为治疗剂具有吸引力，并且一些研究者报告了通过使用AS策略在体外和体内抑制SMC增殖的现象。我们在这里报告使用针对c-myb和c-myc的AS寡核苷酸对血管SMC进行实验的结果。我们发现，这些特定的AS序列对SMC增殖产生了明显的抑制作用，但这种抑制作用显然不是通过依赖杂交的AS机制进行的。相反，抑制是由于寡核苷酸序列中存在四个连续的鸟苷残基。这在SMC的原代培养中和离体动脉中得到了体外证明。这里开发的离体模型提供了一种快速有效的系统，可在其中筛选潜在的寡核苷酸药物用于再狭窄。我们进一步探索了这种非AS效应的序列要求，并确定了含有至少两组三个或四个连续鸟苷残基的硫代磷酸酯寡核苷酸在体外和离体均可抑制SMC增殖。这些结果表明，使用这些和相似的，连续的含鸟苷的AS序列获得的先前的AS数据应重新评估，并且可能还有另一类具有抗再狭窄治疗潜力的核酸化合物。

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