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A Disaccharide-Based Inhibitor of Glycosylation Attenuates Metastatic Tumor Cell Dissemination

Authors' Affiliations: ¹ Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center; ² Department of Medicine, Division of Pulmonary and Critical Care; and ³ Department of Pathology, University of California, San Diego, La Jolla, California

Requests for reprints: Jeffrey D. Esko, Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0687. Phone: 858-822-1100; Fax: 585-534-5611; E-mail: jesko{at}ucsd.edu.

Purpose: The binding of hematogenously borne malignant cells that express the carbohydrate sialyl Lewis X (sLe^X) to selectin adhesion receptors on leukocytes, platelets, and endothelial cells facilitates metastasis. The glycosylation inhibitor, per-O-acetylated GlcNAcß1,3Galß-O-naphthalenemethanol (AcGnG-NM), inhibits the biosynthesis of sLe^X in tumor cells. To evaluate the efficacy of AcGnG-NM as an antimetastatic agent, we examined its effect on experimental metastasis and on spontaneous hematogenous dissemination of murine Lewis lung carcinoma and B16BL6 melanoma cells.

Experimental Design: Tumor cells were treated in vitro with AcGnG-NM, and the degree of selectin ligand inhibition and experimental metastasis was analyzed in wild-type and P-selectin-deficient mice. Conditions were developed for systemic administration of AcGnG-NM, and the presence of tumor cells in the lungs was assessed using bromodeoxyuridine labeling in vivo. The effect of AcGnG-NM on inflammation was examined using an acute peritonitis model.

Results: In vitro treatment of Lewis lung carcinoma cells with AcGnG-NM reduced expression of sLe^X- and P-selectin-dependent cell adhesion to plates coated with P-selectin. Treatment also reduced formation of lung foci when cells were injected into syngeneic mice. Systemic administration of the disaccharide significantly inhibited spontaneous dissemination of the cells to the lungs from a primary s.c. tumor, whereas an acetylated disaccharide not related to sLe^X in structure had no effect. AcGnG-NM did not alter the level of circulating leukocytes or platelets, the expression of P-selectin ligands on neutrophils, or sLe^X-dependent inflammation.

Conclusion: Taken together, these data show that AcGnG-NM provides a targeted glycoside-based therapy for the treatment of hematogenous dissemination of tumor cells.

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