锁定核酸反义寡核苷酸EZN-3042对体内生存素表达的下调及肿瘤生长的抑制作用

Down-modulation of survivin expression and inhibition of tumor growth in vivo by EZN-3042, a locked nucleic acid antisense oligonucleotide.

作者信息

Sapra Puja, Wang Maoliang, Bandaru Raj, Zhao Hong, Greenberger Lee M, Horak Ivan D

机构信息

Enzon Pharmaceuticals, Inc., Piscataway, New Jersey, USA.

出版信息

Nucleosides Nucleotides Nucleic Acids. 2010 Feb;29(2):97-112. doi: 10.1080/15257771003597733.

DOI:10.1080/15257771003597733

PMID:20391197

Abstract

Survivin plays an important role in preventing apoptosis and permitting mitosis, and is highly expressed in various human cancers. EZN-3042 is a locked nucleic acid antisense oligonucleotide (LNA-AsODN) against survivin. We report the effects of EZN-3042 in animal models. In a chemical-induced liver regeneration model, treatment with a mouse homolog of EZN-3042 resulted in 80% down-modulation of survivin mRNA. In A549 and Calu-6 lung xenograft models, treatment with EZN-3042 single agent induced 60% down-modulation of survivin mRNA in tumors and 37-45% tumor growth inhibition (TGI). In Calu-6 model, when EZN-3042 was combined with paclitaxel, an 83% TGI was obtained. EZN-3042 is currently being evaluated in a Phase 1 clinical trial as a single agent and in combination with docetaxel.

摘要

存活素在防止细胞凋亡和促进有丝分裂过程中发挥重要作用，且在多种人类癌症中高表达。EZN - 3042是一种针对存活素的锁核酸反义寡核苷酸（LNA - AsODN）。我们报告了EZN - 3042在动物模型中的作用效果。在化学诱导的肝再生模型中，用EZN - 3042的小鼠同源物进行治疗导致存活素mRNA下调80%。在A549和Calu - 6肺异种移植模型中，用EZN - 3042单药治疗可使肿瘤中存活素mRNA下调60%，并使肿瘤生长抑制（TGI）达37 - 45%。在Calu - 6模型中，当EZN - 3042与紫杉醇联合使用时，肿瘤生长抑制率达83%。目前，EZN - 3042正在作为单药以及与多西他赛联合使用进行1期临床试验评估。