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

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.
Authors	Puja Sapra, Maoliang Wang, Raj Bandaru, Hong Zhao, Lee M Greenberger, Ivan D Horak
Journal	Nucleosides, nucleotides & nucleic acids (Nucleosides Nucleotides Nucleic Acids) Vol. 29 Issue 2 Pg. 97-112 (Feb 2010) ISSN: 1532-2335 [Electronic] United States
PMID	20391197 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	BIRC5 protein, human EZN 3042 Inhibitor of Apoptosis Proteins Microtubule-Associated Proteins Oligonucleotides Oligonucleotides, Antisense RNA, Messenger Survivin locked nucleic acid Paclitaxel
Topics	Animals Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use) Cell Line, Tumor Cell Proliferation (drug effects) Disease Models, Animal Down-Regulation (drug effects, genetics) Female Gene Expression Regulation, Neoplastic (drug effects) Humans Inhibitor of Apoptosis Proteins Liver Regeneration (drug effects) Lung Neoplasms (drug therapy, genetics, pathology) Maximum Tolerated Dose Mice Mice, Inbred BALB C Mice, Nude Microtubule-Associated Proteins (genetics, metabolism) Oligonucleotides (pharmacology, therapeutic use) Oligonucleotides, Antisense (pharmacology, therapeutic use) Paclitaxel (pharmacology, therapeutic use) RNA, Messenger (genetics, metabolism) Survivin Treatment Outcome Xenograft Model Antitumor Assays

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