β-catenin antisense treatment decreases β-catenin expression and tumor growth rate in colon carcinoma xenografts

Background. Loss of the adenomatous polyposis coli (APC) tumor suppresser 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. (C) 2001 Academic Press.