The prognosis of colorectal cancer is adversely affected by liver metastasis, and therapeutic options are limited for advanced disease. Rolling of carcinoma cells along vascular endothelium is mediated through selectin adhesion receptors and their ligands, sialyl Lewis x (sLex) and sialyl Lewis a (sLea). Biosynthesis of these glycans on human colon cancer cells is largely controlled by the alpha(1,3)fucosyltransferases FUT3 and FUT6. Stable transfection of carcinoma cells with antisense FUT3/FUT6 sequences inhibits expression of sLex/sLea, selectin-mediated adhesion, and liver metastasis in nude mice. The proposed experiments extend these results to an in vivo pre-clinical model with FUT antisense oligodeoxynucleotides (AS-ODNs) against highly metastatic HT29-LMM colon carcinoma cells and locally invasive, non-metastatic COLO-205 colon cancer cells. The long-term goals are to extend the use of AS-ODNs to adjunctive treatment of colon carcinoma metastasis and to contribute to the study of glycosyltransferase gene regulation.
