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 suppresser g ene plays a significant role in colorectal carcinogenesis. One function of the APC gene product is to regulate beta -catenin, a protein that plays a r ole in cell adhesion and also regulates the activity of certain transcripti on factors. To more precisely delineate the role of beta -catenin signaling in colon cancer growth, we treated mice bearing APC-mutant SW480 colon can cer xenografts with antisense oligonucleotides (ODNs) directed against beta -catenin mRNA and examined effects on beta -catenin expression and tumor g rowth. Methods. Balb/C nude mice underwent subcutaneous injection of 1 x 10(6) SW4 80 cells to establish tumor xenografts. In one experiment, tumors were allo wed 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 tumo r lysates subjected to gel electrophoresis and Western blotting for beta -c atenin protein quantification. In a second experiment, tumor-bearing animal s began receiving daily intraperitoneal injections of either antisense beta -catenin ODN at doses of 5, 10, or 20 mg/kg, scrambled sequence beta -cate nin ODN control, or saline control. Tumor growth was quantitated by measuri ng tumor volumes twice weekly. A third experiment evaluated the antitumor e ffects of daily bolus dosing versus continuous infusion of beta -catenin an tisense 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 -ca tenin protein expression as shown by Western blotting. Treatment of tumor-b earing mice with antisense directed at beta -catenin also demonstrated a do se-dependent inhibition of tumor growth. There appears to be little differe nce in the antitumor effects of antisense ODNs administered by continuous i nfusion or bolus dosing schedules. Conclusions. beta -Catenin expression plays a critical role in the tumorige nic growth of APC-mutant colon cancer xenografts. Strategies targeting beta -catenin, including the use of antisense ODNs, may be of use in the treatm ent of human colon cancer. (C) 2001 Academic Press.