Gewirtz A M
Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Ciba Found Symp. 1997;209:169-91; discussion 191-4.
The concept of antisense oligonucleotide 'therapeutics' has generated a great deal of controversy. Questions abound regarding the mechanism of action of these compounds, their reliability and their ultimate utility. These problems are compounded by the 'hype', which has attended their development, and the inability of workers in this area to meet the expectations raised by its most zealous proponents. Nevertheless, it is worth pointing out that there have been some notable gene disruption successes with this technique that have stood up to rigorous scrutiny. Our own work with c-myb as a target is perhaps a reasonable example. Though much remains to be accomplished before antisense drugs are commonly, and usefully, employed in the clinic, it is important to remember what motivates their development. Gene-targeted drugs have the promise of exquisite specificity and the potential to do much good with little toxicity. Accordingly, antisense oligonucleotides can serve as a paradigm of rational drug development. For all these reasons then, we believe that efforts should be increased to decipher the mechanism of action of antisense oligodeoxynucleotides, and to learn how they may be successfully employed in the clinic.
反义寡核苷酸“疗法”的概念引发了诸多争议。关于这些化合物的作用机制、可靠性及其最终效用，存在诸多问题。这些问题因该领域发展过程中的“炒作”以及该领域研究人员无法满足其最狂热支持者所提出的期望而变得更加复杂。然而，值得指出的是，这项技术已经取得了一些显著的基因破坏成功案例，并且经过了严格审查。我们自己以c-myb为靶点的研究工作或许就是一个恰当的例子。尽管在反义药物能够在临床上普遍且有效地应用之前，仍有许多工作要做，但重要的是要记住推动其发展的因素。基因靶向药物有望具有极高的特异性，并且有可能在低毒性的情况下带来诸多益处。因此，反义寡核苷酸可以作为合理药物开发的一个范例。基于所有这些原因，我们认为应该加大力度来破解反义寡脱氧核苷酸的作用机制，并了解如何在临床上成功应用它们。
