Beta-catenin antisense treatment decreases beta-catenin expression and tumor growth rate in colon carcinoma xenografts.
BACKGROUND
Loss of the adenomatous polyposis coli (APC) tumor suppressor gene plays a significant role in colorectal carcinogenesis. One function of the APC gene product is to regulate beta-catenin, a protein that plays a role in cell adhesion and also regulates the activity of certain transcription factors. To more precisely delineate the role of beta-catenin signaling in colon cancer growth, we treated mice bearing APC-mutant SW480 colon cancer xenografts with antisense oligonucleotides (ODNs) directed against beta-catenin mRNA and examined effects on beta-catenin expression and tumor growth.


METHODS
Balb/C nude mice underwent subcutaneous injection of 1 x 10(6) SW480 cells to establish tumor xenografts. In one experiment, tumors were allowed to grow for 7 days, after which time animals were randomized to undergo daily intraperitoneal injections of either antisense beta-catenin ODN at doses of 5, 10, or 20 mg/kg, scrambled sequence beta-catenin ODN control, or saline control for 7 days. Tumors were excised and homogenized, and tumor lysates subjected to gel electrophoresis and Western blotting for beta-catenin protein quantification. In a second experiment, tumor-bearing animals began receiving daily intraperitoneal injections of either antisense beta-catenin ODN at doses of 5, 10, or 20 mg/kg, scrambled sequence beta-catenin ODN control, or saline control. Tumor growth was quantitated by measuring tumor volumes twice weekly. A third experiment evaluated the antitumor effects of daily bolus dosing versus continuous infusion of beta-catenin antisense ODNs (20 mg/kg).


RESULTS
Treatment of APC-mutant colorectal carcinoma xenografts with beta-catenin antisense resulted in a dose-dependent down-regulation in beta-catenin protein expression as shown by Western blotting. Treatment of tumor-bearing mice with antisense directed at beta-catenin also demonstrated a dose-dependent inhibition of tumor growth. There appears to be little difference in the antitumor effects of antisense ODNs administered by continuous infusion or bolus dosing schedules.


CONCLUSIONS
beta-Catenin expression plays a critical role in the tumorigenic growth of APC-mutant colon cancer xenografts. Strategies targeting beta-catenin, including the use of antisense ODNs, may be of use in the treatment of human colon cancer.
Green
D W
DW
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Roh
H
H
Pippin
J A
JA
Drebin
J A
JA
D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005260:Female; D017491:Genes, APC; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D015534:Trans-Activators; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000637:transplantation; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D016376:Oligonucleotides, Antisense; D015534:Trans-Activators; D051176:beta Catenin