Clustered presentation of
sialyl Lewis X (
sLe(X)) on
tumor cell
mucins is thought to facilitate
metastasis through binding to
selectin adhesion receptors expressed on platelets, leukocytes and endothelial cells. Thus, interfering with
sLe(X) assembly might provide a chemotherapeutic method for treating metastatic disease. Prior studies have shown that peracetylated
disaccharides can act in cells as substrates for the assembly of
oligosaccharides related to
sLe(X) synthesis, and the assembly of
oligosaccharides on the
disaccharides diverts the assembly of
sLe(X) from endogenous cell surface
glycoconjugates. Here, we show that treatment of cultured human
adenocarcinoma cells with micromolar concentrations of the peracetylated
disaccharide,
(Ac)(6)GlcNAcbeta1,3Galbeta-O-naphthalenemethanol (
AcGnG-NM) reduces the expression of
sLe(X) and diminishes binding in vitro to
selectin-coated dishes,
thrombin-activated platelets, and
tumor necrosis factor alpha-activated endothelial cells. Altering glycosylation in this way significantly reduced the ability of
tumor cells to distribute to the lungs of wild-type mice over a 3-h period after i.v. injection. No significant difference in biodistribution was noted after the injection of
AcGnG-NM-treated
tumor cells into
P-selectin deficient mice, although the extent of lung seeding was reduced compared with that in wild-type mice. In vitro, we demonstrate that normal mouse platelets, but not
P-selectin-deficient platelets, bound to control
tumor cells and protected them from leukocyte-mediated cytolysis. Conversely, treatment of
tumor cells with
disaccharide markedly reduced the ability of normal platelets to protect them from cytolysis. Finally, in an experimental
metastasis model, we show that treatment of
tumor cells with the
disaccharide markedly reduced their lung colonization potential after injection into severe combined immunodeficient mice. These findings suggest that this compound may represent a novel class of chemotherapeutic agents for prevention and treatment of metastatic disease.