Suppression of beta-catenin by antisense oligomers augments tumor response to isolated limb perfusion in a rodent model of adenomatous polyposis coli-mutant colon cancer.
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 beta-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 beta-catenin, (5) ILP with nonspecific antisense, and (6) melphalan plus beta-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 beta-catenin-specific ILP, 13% +/- 19% for nonspecific antisense ILP, and 73% +/- 6% for melphalan plus beta-catenin-specific ILP (P < .05 for melphalan ILP, beta-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 beta-catenin-specific ILP, 10 days after nonspecific antisense ILP, and 60 days after melphalan plus beta-catenin-specific ILP (P < .05 for melphalan plus beta-catenin-specific ILP compared with all others). Western blotting revealed prolonged suppression of beta-catenin expression after beta-catenin-specific ILP.


CONCLUSIONS
Short-term beta-catenin antisense treatment improves tumor response rates after ILP in a rodent model of human CRC.
Canter
Robert J
RJ
Department of Surgery, University of Pennsylvania School of Medicine, 3400 Spruce Street, 4 Silverstein, Philadelphia, Pennsylvania, 19104, USA.
Kesmodel
Susan B
SB
Heitjan
Daniel F
DF
Veeramachaneni
Nirmal K
NK
Mokadam
Nahush A
NA
Drebin
Jeffrey A
JA
Fraker
Douglas L
DL
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics; D011125:Adenomatous Polyposis Coli / Q000150:complications / Q000235:genetics; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D045744:Cell Line, Tumor; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000379:methods; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D005121:Extremities; D005260:Female; D015316:Genetic Therapy; D008558:Melphalan / Q000008:administration & dosage; D023421:Models, Animal; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage*; D051381:Rats; D012074:Remission Induction; D051176:beta Catenin / Q000378:metabolism*
D018906:Antineoplastic Agents, Alkylating; D020319:Oligodeoxyribonucleotides, Antisense; D051176:beta Catenin; D008558:Melphalan