Heparin is an excellent inhibitor of P-and L-selectin binding to the carbohydrate determinant, sialyl Lewis x . As a consequence of its anti-selectin activity, heparin attenuates metastasis and inflammation. Here we show that fucosylated chondroitin sulfate (FucCS), a polysaccharide isolated from sea cucumber composed of a chondroitin sulfate backbone substituted at the 3-position of the ␤-D-glucuronic acid residues with 2,4-disulfated ␣-L-fucopyranosyl branches, is a potent inhibitor of P-and L-selectin binding to immobilized sialyl Lewis x and LS180 carcinoma cell attachment to immobilized P-and L-selectins. Inhibition occurs in a concentration-dependent manner. Furthermore, FucCS was 4 -8-fold more potent than heparin in the inhibition of the P-and L-selectin-sialyl Lewis The surface of carcinoma cells exhibits altered glycosylation patterns (1-5), often containing highly branched or sialylated oligosaccharides, especially fucosylated glycans such as sialylLewis X (Sia␣2-3Gal␤1-4(Fuc␣1-3)GlcNAc) and sialyl-Lewis a (Sia␣2-3Gal␤1-3(Fuc␣1-4)GlcNAc). The presence of these oligosaccharides in tumor cells directly correlates with a poor prognosis for cancer patients because of tumor progression and metastatic spread (1-5). The sLe X -oligosaccharides 4 from carcinoma cells act as ligands of the three members of the selectin family of cell adhesion molecules. E-, P-, and L-selectins are vascular receptors for certain normal glycoproteins that contain sialyl-Lewis x,a found on leukocytes and endothelium (6 -8). The selectins also participate in hematogenous metastasis by mediating the interactions of tumor cells with platelets and endothelium (1-3). Hematogenous metastasis occurs through a series of sequential events involving the intravasation of tumor cells into the bloodstream, evasion of innate immune surveillance, adhesion to vascular endothelium of distant organs with subsequent extravasation, and colonization of tissues. It has been proposed that these microemboli of tumor cells with platelets and leukocytes allow tumor cells to evade the immune defenses and eventually colonize distant organs, forming metastatic foci (9 -15). Several studies have shown that a few minutes after intravenous injection, tumor cells are detected in emboli inside pulmonary capillaries in association with platelets and fibrin.Studies from several groups have indicated that tumor metastasis in experimental animals is inhibited by heparin (16 -19). Some clinical studies have also shown a beneficial effect of heparin in some types of human cancer (20 -24). The antimetastatic effect of heparin does not reflect its anticoagulant activity (25, 26) but rather relates to the ability of heparin to inhibit the interaction of sialyl Lewis x,a -rich oligosaccharides on tumor cells with P-selectin on platelets (16,27). In the presence of heparin, tumor cells lose the protection conferred by platelets becoming susceptible to the potentially cytotoxic action of immune effector cells, which leads to the inhibition of metastasis. A single intravascul...

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Heparin is an intracellular product of vertebrate mast cell currently used as exogenous anticoagulant. Despite of the potent biological activities of exogenous heparin, its physiological function has not been clearly established yet. Here, a heparin with similar structure and anticoagulant properties to the mammalian counterpart was shown to occur as the intracellular product of test cells, a cell monolayer that surrounds egg of the invertebrate Styela plicata (Chordata-Tunicata). As in the case of mammalian mast cells, heparin from the ascidian test cells is removed from the intracellular granules after incubation with compound 48/80. Following fertilization, the test cells surrounding the developing larva still retain heparin as metachromatic granulation. In the adult invertebrate, heparin occurs as intracellular granules at the apical tip of epithelial cells surrounding the lumen of both intestine and pharynx, in close contact with the external environment. This is the first description of the presence of heparin in cytoplasmic granules of epithelial-like cells around the lumen of sites exposed to external agents. This arrangement may reflect the participation of heparin in defense mechanisms in this invertebrate.

Chemotherapy-induced mucositis is an important dose-limiting and costly side effect for which there is no definitive prophylaxis or treatment. This is due in part to the lack of understanding of its pathophysiology and impact on intestinal function. The objectives of this study were to investigate the small intestine barrier function and electrolyte and water transport in an experimental model of methotrexate-induced mucositis, and to correlate these alterations with histological damage. Wistar rats were treated with methotrexate (1.5-3.5 mg/kg) for 3 days to induce mucositis. Intestinal permeability was measured by the urinary excretion rate of lactulose and mannitol following administration by gavage. Intestinal perfusion was performed in vivo for evaluation of water and electrolyte transports. Methotrexate-treated rats lost a significant amount of weight and presented a marked reduction in food intake. Methotrexate induced significant and dose-dependent villous atrophy and elongation of crypts in duodenum, jejunum, and ileum. Methotrexate also induced an increase in sodium and potassium secretion and an important reduction of the mucosa absorptive surface area, shown by the decrease in the mannitol excretion ratio. In conclusion, methotrexate caused major changes in small bowel function by disrupting intestinal permeability and inducing electrolyte secretion in parallel with substantial histological damage.