A disaccharide-based inhibitor of glycosylation attenuates metastatic tumor cell dissemination.

Abstract

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 GlcNAcbeta1,3Galbeta-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.

• Authors: Jillian R Brown, Mark M Fuster, Ruixia Li, Nissi Varki, Charles A Glass, Jeffrey D Esko
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 9 Pg. 2894-901 (May 01 2006) ISSN: 1078-0432 [Print] United States
• PMID: 16675586 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Disaccharides

Topics

• Animals
• Antineoplastic Agents (chemistry, therapeutic use)
• Disaccharides (chemistry, therapeutic use)
• Glycosylation (drug effects)
• Melanoma, Experimental (pathology)
• Mice
• Neoplasm Metastasis (prevention & control)