Suppression of β-catenin by antisense oligomers augments tumor response to isolated limb perfusion in a rodent model of adenomatous polyposis coli-mutant colon cancer

Abstract

Background: Isolated hepatic perfusion has been used in patients with colorectal cancer (CRC) metastatic to the liver. We sought to determine whether perfusion with antisense oligodeoxynucleotides results in the downregulation of β-catenin and whether this improves tumor response to isolated limb perfusion (ILP) in a heterotopic model of human CRC. Methods: Adenomatous polyposis coli-mutant human CRC xenografts were implanted into athymic rats. Animals were randomized to the following groups: (1) no treatment, (2) control ILP, (3) melphalan ILP, (4) ILP with antisense specific for β-catenin, (5) ILP with nonspecific antisense, and (6) melphalan plus β-catenin-specific antisense ILP. Tumor response and Western blot analysis of protein expression were evaluated. Results: The maximal decrease (mean ± SE) in tumor volume was 0% ± 10% for no treatment, 19% ± 14% for control ILP, 58% ± 3% for melphalan ILP, 58% ± 9% for β-catenin-specific ILP, 13% ± 19% for nonspecific antisense ILP, and 73% ± 6% for melphalan plus β-catenin-specific ILP (P < .05 for melphalan ILP, β-catenin-specific ILP, and melphalan plus antisense ILP). Tumor regrowth was delayed for 6 days after control ILP, 24 days after melphalan ILP, 20 days after β-catenin-specific ILP, 10 days after nonspecific antisense ILP, and 60 days after melphalan plus β-catenin-specific ILP (P < .05 for melphalan plus β-catenin-specific ILP compared with all others). Western blotting revealed prolonged suppression of β-catenin expression after β-catenin-specific ILP. Conclusions: Short-term β-catenin antisense treatment improves tumor response rates after ILP in a rodent model of human CRC. © 2005 The Society of Surgical Oncology, Inc.