Crooke S T, Bennett C F
Isis Pharmaceuticals, Inc., Carlsbad, California 92008, USA.
Annu Rev Pharmacol Toxicol. 1996;36:107-29. doi: 10.1146/annurev.pa.36.040196.000543.
The past several years have seen substantial progress in the development of antisense oligonucleotides as pharmacological tools and as therapeutic agents. With properly designed and executed experiments, it has been possible to demonstrate selective inhibition of gene expression, owing to an antisense mechanisms of action both in cell culture-based experiments and in vivo. As the field has matured, it has also realized that oligonucleotides can produce a variety of effects in cell culture and in vivo that cannot be ascribed to an antisense mechanism of action. Nevertheless, with proper controls it has been possible to demonstrate that the pharmacological activity of an oligonucleotide is consistent with an antisense mechanism of action. The pharmacokinetic properties of first-generation phosphorothioate oligodeoxynucleotides and their toxicological limitations have been characterized in rodents, primates, and humans. Finally, it has been demonstrated that medicinal chemistry can improve the properties of oligonucleotides, as several modifications have been identified that have increased potency, altered pharmacokinetic properties and potentially decreased toxicological liabilities.
在过去几年中，反义寡核苷酸作为药理学工具和治疗剂的开发取得了重大进展。通过设计合理且执行得当的实验，无论是在基于细胞培养的实验中还是在体内，由于反义作用机制，都能够证明基因表达的选择性抑制。随着该领域的成熟，人们也认识到寡核苷酸在细胞培养和体内可产生多种无法归因于反义作用机制的效应。然而，通过适当的对照，已能够证明寡核苷酸的药理活性与反义作用机制一致。第一代硫代磷酸酯寡脱氧核苷酸的药代动力学特性及其毒理学局限性已在啮齿动物、灵长类动物和人类中得到表征。最后，已经证明药物化学可以改善寡核苷酸的特性，因为已鉴定出几种修饰，这些修饰提高了效力、改变了药代动力学特性并可能降低了毒理学风险。
