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Ajit Varki

Publications and source records attributed to Ajit Varki.

59 records · Page 4Linked to original sources
PubMed2002

Heparin inhibition of selectin-mediated interactions during the hematogenous phase of carcinoma metastasis: rationale for clinical studies in humans.

Classic studies indicate that the formation of tumor cell-platelet complexes in the blood stream is important in facilitating the metastatic process. Metastasis in animal models can be inhibited by heparin, and retrospective analyses of heparin use in human cancer have shown promise. However, most follow-up human studies using vitamin K antagonists have failed, and conclusive proof for other previously proposed mechanisms of heparin action is lacking. Carcinoma progression and metastasis are associated with overexpression of sialylated fucosylated mucins. Structurally similar molecules happen to be natural ligands for vascular adhesion molecules called the selectins. Heparin also happens to be a good inhibitor of P-selectin, which is expressed on activated platelets or endothelial cells. We have found that heparin blocks P-selectin-mediated interactions of endogenous platelets with sialylated fucosylated mucins on circulating carcinoma cells and that this reduces tumor cell survival. The use of more specific and selective P-selectin inhibitors will some day help to dissect the relative importance of this mechanism of heparin action in cancer. Meanwhile, we suggest that the failure of vitamin K antagonists to improve cancer prognosis should be ignored and that heparin therapy should be immediately revisited under this new paradigm. Unlike the suggestions in most previous studies, we propose that heparin use should be reexplored specifically during the interval from initial visualization of a primary tumor until just after its definitive surgical removal. A suggested clinical trial is outlined.

Animals↗
PubMed2002

Generation of mice deficient for macrophage galactose- and N-acetylgalactosamine-specific lectin: limited role in lymphoid and erythroid homeostasis and evidence for multiple lectins.

Macrophage receptors function in pattern recognition for the induction of innate immunity, in cellular communication to mediate the regulation of adaptive immune responses, and in the clearance of some glycosylated cells or glycoproteins from the circulation. They also function in homeostasis by initiating the engulfment of apoptotic cells. Evidence has suggested that macrophage receptors function to recognize cells that are destined for programmed cell death but not yet overtly apoptotic. We have examined the function of a macrophage receptor specific for unsialylated glycoproteins, known as the mouse macrophage galactose- and N-acetylgalactosamine-specific lectin (mMGL) (Ii et al., J. Biol. Chem. 265:11295-11298, 1990; Sato et al., J. Biochem. [Tokyo] 111:331-336, 1992; Yamamoto et al., Biochemistry 33:8159-8166, 1994). With targeted disruption, we tested whether mMGL is necessary for macrophage function, controlled thymic development, the loss of activated CD8 T cells, and the turnover of red blood cells. Evidence indicates that mMGL may play a nonessential role in several of these macrophage functions. Experiments are presented that indicate the existence of another galactose- and N-acetylgalactosamine-recognizing lectin distinct from mMGL. This may explain the absence of a strong phenotype in mMGL-deficient mice.

Animals↗
PubMed2002

Heparin's anti-inflammatory effects require glucosamine 6-O-sulfation and are mediated by blockade of L- and P-selectins.

Heparin has been used clinically as an anticoagulant and antithrombotic agent for over 60 years. Here we show that the potent anti-inflammatory property of heparin results primarily from blockade of P-selectin and L-selectin. Unfractionated heparin and chemically modified analogs were tested as inhibitors of selectin binding to immobilized sialyl Lewis(X) and of cell adhesion to immobilized selectins or thrombin-activated endothelial cells. Compared with unfractionated heparin, the modified heparinoids had inhibitory activity in this general order: over-O-sulfated heparin > heparin > 2-O,3-O-desulfated > or = N-desulfated/N-acetylated heparin > or = carboxyl-reduced heparin > or= N-,2-O,3-O-desulfated heparin >> 6-O-desulfated heparin. The heparinoids also showed similar differences in their ability to inhibit thioglycollate-induced peritonitis and oxazolone-induced delayed-type hypersensitivity. Mice deficient in P- or L-selectins showed impaired inflammation, which could be further reduced by heparin. However, heparin had no additional effect in mice deficient in both P- and L-selectins. We conclude that (a) heparin's anti-inflammatory effects are mainly mediated by blocking P- and L-selectin-initiated cell adhesion; (b) the sulfate groups at C6 on the glucosamine residues play a critical role in selectin inhibition; and (c) some non-anticoagulant forms of heparin retain anti-inflammatory activity. Such analogs may prove useful as therapeutically effective inhibitors of inflammation.

Animals↗