alpha-Neup5Ac-(2--3)-beta-D-Galp-(1--4)-[alpha-L-Fucp-(1--3)]-D-GlcpNAc and Lymphoma

Macrosphelide B (MSB), a 16-membered macrolide from Microsphaeropsis sp. FO-5050, inhibits adhesion of sialyl Lewis(x) (sLe(x))-expressing HL-60 cells to LPS-activated (E-selectin-expressing) human umbilical vein endothelial cells (HUVECs) in vitro. This study examines MSB effects on metastasis of B16/BL6 mouse melanoma cells (B16/BL6 cells) and L5178Y-ML mouse lymphoma cells in vivo and analyzes the MSB antimetastatic activity mechanism. When administered MSB at 20 mg/kg/day, lung metastatic nodules of B16/BL6 cells were significantly decreased (T/C = 45%). However, no inhibition of metastasis of L5178Y-ML cells to the spleen and liver was observed. Flow cytometry analysis showed that B16/BL6 cells expressed high levels of sLe(x) antigen, whereas expression on L5178Y-ML cells was low. Under in vitro conditions, B16/BL6 cells demonstrated a greater degree of adhesion to LPS-activated HUVECs than L5178Y-ML cells, but adhesion was significantly inhibited by MSB and sLe(x) antibody. Combined therapy of MSB and cisplatin (CDDP) induced remarkable lung metastasis inhibition without adverse effects of CDDP to the host. All these findings suggest that MSB suppresses lung metastasis of B16/BL6 cells by inhibiting cell adhesion to endothelial cells through the sLe(x) molecule.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Adhesion; Cell Adhesion Molecules; Cell Division; Cells, Cultured; Cisplatin; Dose-Response Relationship, Drug; E-Selectin; Endothelium, Vascular; Heterocyclic Compounds; HL-60 Cells; Humans; Lymphoma; Melanoma, Experimental; Mice; Neoplasm Metastasis; Oligosaccharides; Sialyl Lewis X Antigen

E- and P-selectins, expressed on vascular endothelium, and their sialyl-Lewis(x )(sLe(x))- and/or sialyl-Lewis(a) (sLe(a))-containing ligands have a crucial role in extravasation and metastasis of circulating cells. We wanted to analyse the role of selectins and their ligands in head and neck tumours.. A total of 40 consecutive biopsy specimens were collected from surgery performed at the Helsinki University Central Hospital between September 1995 and November 1996. The series of specimens contained both benign and malignant head and neck tumours of epithelial, lymphoid or mesenchymal origin. All these were analysed with immunohistochemistry for epithelial and endothelial expression of sLe(x) and sLe(a) glycans and E- and P-selectins.. Epithelial expression of sLe(x) and sLe(a) glycans was higher in benign than in malignant lesions in both epithelial and lymphoid tumours. On the other hand, endothelial expression of sLe(x), sLe(a), E- and P-selectin was lower in benign than in malignant lesions in both epithelial and lymphoid tumours.. These data suggest that altered epithelial and endothelial expression of sLe(x) and sLe(a )glycans acting on selectin ligands is linked to the development of head and neck tumours.

Topics: Biomarkers, Tumor; CA-19-9 Antigen; Carcinoma; E-Selectin; Endothelium, Vascular; Gangliosides; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Immunoenzyme Techniques; Ligands; Lymphoma; Mesenchymoma; Oligosaccharides; P-Selectin; Polysaccharides; Selectins; Sialyl Lewis X Antigen

We have investigated the inhibitory mechanism of the initial arrest of L5178Y-ML25 lymphoma cells in a target organ (liver) by using recombinant fibronectin fragments with cell- and/or heparin-binding domains (C-274, H-271 or the fusion fragment CH-271). Pretreatment of hepatic sinusoidal endothelial (HSE) cell monolayers with lymphoma cells or their conditioned medium for 4 to 6 h resulted in the enhancement of lymphoma cell adhesion to HSE cell monolayer. The increased tumor adhesiveness was completely abolished by preincubation of the conditioned medium with anti interleukin-1 beta monoclonal antibody (mAb). Synthetic sialyl Le(x) (SLe(x)) as a ligand for endothelial cell leukocyte adhesion molecule-1 (ELAM-1) adhesion receptor and anti ELAM-1 mAb blocked the conditioned medium-induced enhancement of tumor-endothelial cell interaction, while pretreatment of the activated HSE cell monolayer with anti vascular cell adhesion molecule-1 (VCAM-1) mAb did not affect the enhanced tumor cell adhesion. These results indicate that tumor cell interaction with the stimulated HSE cells is mediated by ELAM-1 molecules on HSE cells. However, the expression of SLe(x) and SLe(a) on the tumor surface was not observed by flow cytometric analysis. ELAM-1-mediated enhancement of tumor cell adhesion to HSE monolayer was also inhibited in a concentration-dependent manner by CH-271 fusion polypeptide or the sulfated chitin derivative sulfated carboxymethyl-chitin, which can bind to the heparin-binding domain of CH-271. In addition, CH-271 inhibited not only tumor-endothelium interaction but also tumor cell invasion into reconstituted basement membrane Matrigel in vitro.

Topics: Animals; Antibodies, Monoclonal; Basement Membrane; Carbohydrate Sequence; Cell Adhesion; Cell Adhesion Molecules; Culture Media, Conditioned; E-Selectin; Endothelium, Vascular; Fibronectins; Interleukin-1; Liver; Liver Neoplasms; Lymphoma; Mice; Molecular Sequence Data; Neoplasm Invasiveness; Oligosaccharides; Recombinant Fusion Proteins; Recombinant Proteins; Sialyl Lewis X Antigen; Tumor Cells, Cultured