3000

MMP-7, a member of the matrix metalloproteinase (MMP) family, is thought to play a key role in tumor invasion and metastasis. We have shown that MMP-7 was more highly expressed in metastatic and primary tumors than in normal mucosa in colorectal cancer patients. Therefore, MMP-7 makes a promising target in the development of anticancer therapy. The aim of this study is to evaluate inhibitory effects of YCU2650, a 15-mer antisense phosphorothioate oligonucleotide targeted against translational starting site of MMP-7 mRNA, on human colon cancer cell invasion in vitro and in a murine metastatic model. RESULTS: RT-PCR and Western blot analysis demonstrated that YCU2650 decreased MMP-7 expression at both mRNA (90% inhibition) and protein (60%) levels in human colon cancer cell CaR-1 and WiDR. In vitro invasion assay using Matrigel-coated membrane showed that 10 μM of YCU2650 inhibited the invasive activity of CaR-1 by 50%. Injection of WiDR into the spleen of nude mice produced a number of metastatic nodules in the liver, whereas daily intraperitoneal (i.p.) administration of YCU2650 strongly inhibited the formation of metastases in a dose-dependent manner (20-120 μg/mouse). Radio-labeled YCU2650 showed liver accumulation after i.p. and more than 80 % of the accumulated oligomers were intact in form for up to 48 hrs. CONCLUSION: These results suggest a therapeutic potential of YCU2650 for colorectal cancer.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]