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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Disease Models, Animal
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Down-Regulation / drug effects
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Down-Regulation / genetics*
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Inhibitor of Apoptosis Proteins
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Liver Regeneration / drug effects
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / genetics
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Lung Neoplasms / pathology*
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Maximum Tolerated Dose
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Microtubule-Associated Proteins / genetics*
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Microtubule-Associated Proteins / metabolism
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Oligonucleotides / pharmacology
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Oligonucleotides / therapeutic use*
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Oligonucleotides, Antisense / pharmacology
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Oligonucleotides, Antisense / therapeutic use*
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Paclitaxel / pharmacology
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Paclitaxel / therapeutic use
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Survivin
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Treatment Outcome
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Xenograft Model Antitumor Assays*
Substances
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BIRC5 protein, human
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EZN 3042
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Inhibitor of Apoptosis Proteins
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Microtubule-Associated Proteins
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Oligonucleotides
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Oligonucleotides, Antisense
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RNA, Messenger
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Survivin
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locked nucleic acid
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Paclitaxel