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
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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.
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.
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.
Short-term β-catenin antisense treatment improves tumor response rates after ILP in a rodent model of human CRC.
KeywordsIsolated limb perfusion β-Catenin antisense Adenomatous polyposis coli Hepatic metastases
Supported by the Georgene S. Harmelin Endowment Fund (D.L.F.) and by grants from the National Institutes of Health and the Burroughs Wellcome Fund (J.A.D.).
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