Background: Previously, we showed that short-term inhibition of beta-catenin expression and reversal of aberrant beta-catenin subcellular localization by the selective COX-2 inhibitor celecoxib is associated with adenoma regression in the C57BL/6J Mini+ mouse. Conversly, long-term administration resulted in tumor resistance, leading us to investigate alternative methods for selective beta-catenin chemoprevention. In this study, we hypothesized that disruption of beta-catenin expression by EZN-3892, a selective locked nucleic acid (LNA)-based beta-catenin inhibitor, would counteract the tumorigenic effect of Apc loss in Min/+ adenomas while preserving normal intestinal function. Materials and methods: C57BL/6J Ape(+/+). wild-type (WT) and Min/+ mice were treated with the maximum tolerated dose (MTD) of EZN-3892 (30 mg/kg). Drug effect on tumor numbers, beta-catenin protein expression, and nuclear beta-catenin localization were determined. Results: Although the tumor phenotype and beta-catenin nuclear localization in Min/+ mice did not change following drug administration, we observed a decrease in beta-catenin expression levels in the mature intestinal tissue of treated Min/+ and WT mice, providing proof of principle regarding successful delivery of the LNA-based antisense vehicle. Higher doses of EZN-3892 resulted in fatal outcomes in Min/+ mice, likely due to beta-catenin ablation in the intestinal tissue and loss of function. Conclusions: Our data support the critical role of Wnt/beta-catenin signaling in maintaining intestinal homeostasis and highlight the challenges of effective drug delivery to target disease without permanent toxicity to normal cellular function. (C) 2014 Elsevier Inc. All rights reserved.