Crooke R M, Graham M J, Cooke M E, Crooke S T
Isis Pharmaceuticals, Inc., Carlsbad Research Center, California, USA.
J Pharmacol Exp Ther. 1995 Oct;275(1):462-73.
ISIS 2105 (Afovirsen), a 20-mer phosphorothioate oligonucleotide that inhibits the production of a gene product essential to the growth of human papillomavirus, is in phase II clinical trials for the treatment of genital warts induced by human papillomavirus-6 and human papillomavirus-11. The uptake, subcellular distribution and metabolism of ISIS 2105 and three other similar length phosphorothioates have been studied in a variety of cell lines. Our experiments indicated that ISIS 2105 and other phosphorothioates are internalized and distributed in a time-, temperature-, concentration-, sequence- and cell line-dependent manner. Cell association was also influenced by the tissue culture medium. Several different analytical techniques revealed that phosphorothioates were more rapidly degraded in vitro than previously reported. These data suggest that phosphorothioate oligonucleotide uptake and stability observed in tissue culture can vary as a function of cellular assay conditions and analytical methods used. Comparison of these results with those obtained in vivo suggests that the pharmacokinetic behavior of this class of compounds cannot necessarily be predicted from in vitro studies.
ISIS 2105（阿伏韦生）是一种20聚体硫代磷酸酯寡核苷酸，可抑制人乳头瘤病毒生长所必需的一种基因产物的产生，目前正处于治疗由人乳头瘤病毒6型和人乳头瘤病毒11型引起的尖锐湿疣的II期临床试验阶段。ISIS 2105和其他三种长度相似的硫代磷酸酯的摄取、亚细胞分布及代谢已在多种细胞系中进行了研究。我们的实验表明，ISIS 2105和其他硫代磷酸酯以内化的形式存在，其分布方式取决于时间、温度、浓度、序列及细胞系。细胞结合情况也受组织培养基的影响。几种不同的分析技术表明，硫代磷酸酯在体外的降解速度比之前报道的更快。这些数据表明，在组织培养中观察到的硫代磷酸酯寡核苷酸摄取和稳定性可能会因细胞检测条件和所使用的分析方法不同而有所变化。将这些结果与体内实验结果进行比较表明，这类化合物 的药代动力学行为不一定能通过体外研究来预测。
