Phospholipid- or lipid-linked glycosaminoglycan and process for

Details Phospholipid- or lipid-linked glycosaminoglycan and process for Phospholipid- or lipid-linked glycosaminoglycan and process for

1991-03-24

1995-11-07

Robinson, Douglas W.

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

536 41, 536 171, 536 172, 536 53, 536 54, 536 55, 536 551, 536 553, 536117, 536123, A61K 31725, C08B 3710

Patent

active

054649420

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

This invention relates to phospholipid- or lipid-linked glycosaminoglycans, a process for producing the same and metastasis inhibitors.


BACKGROUND OF THE INVENTION

During the process of metastasis development, it is known that a cancer cell which has strayed into a blood vessel or lymphoduct adheres to an endothelial cell or to its extracellular matrix (so-called basement membrane) and the thus adhered cancer cell permeates into the extra-cellular matrix to develop a new metastatic lesion in the tissue. For example, S. Korach et al. (Cancer Research, 46, 3624-3629, 1986) reported that they have divided cancer cells into a high metastatic group and a low metastatic group and through their cancer cell cloning studies, conducted in vitro adhesion tests of cancer cells to cultured endothelial. As a result, the adhesiveness of cancer cells to blood vessel endothelial cells or to their extra-cellular matrices is closely related to metastasis of cancer cells because the high metastatic group cancer cells showed a high adhesiveness while the low metastatic cells showed a low adhesiveness.
On the other hand, the peptide sequence GRGDS (Gly-Arg-Gly-Asp-Ser) of the cell adhesion moiety of fibronectin which is a component of the extra-cellular matrix, competitively inhibits binding between cancer cells and the extra-cellular matrix. Yamada et al. (Science, 233, 467-470, 1986) reported that the peptide GRGDS inhibited lung metastasis of B16F10 cells in mice. These results indicate that a substance which has cell adhesion inhibitory activity in a small amount could be used as a metastasis inhibitor.
The present invention has been accomplished based on a finding that certain types of phospholipid-or lipid-linked glycosaminoglycans can inhibit adhesion of cancer cells to blood vessel endothelial cells and their extra-cellular matrices and, as a result, can inhibit metastasis of cancer cells.


DESCRIPTION OF THE INVENTION

The present invention relates to phospholipid- or lipid-linked glycosaminoglycans, a process for producing the same and metastasis inhibitors containing the same or the salts thereof.
As shown in Table 1, glycosaminoglycan is a long chain polysaccharide which consists of recurring units of disaccharides or tetrasaccharides including D-glucosamine or D-galactosamine, D-glucuronic acid, L-iduronic acid and/or D-galactose. Examples of known glycosaminoglycan include hyaluronic acid, chondroitin, chondroitin sulfate A, chondroitin sulfate C, chondroitin sulfate D, chondroitin sulfate E, chondroitin sulfate K, chondroitin polysulfate, dermatan sulfate, heparin, heparan sulfate, keratan sulfate and keratan polysulfate.


TABLE 1 ______________________________________ Glycosaminoglycan Hexosamine Uronic acid ______________________________________ Hyaluronic acid GlcNAc GlcUA (MW, 1,000-10,000,000) Chondroitin GalNAc GlcUA (MW, 1,000-100,000) Chondroitin sulfate A GalNAc (4S) GlcUA (MW, 1,000-100,000) Chondroitin sulfate C GalNAc (6S) GlcUA (MW, 1,000-100,000) Chondroitin sulfate D GalNAc (6S) GlcUA (2S) (MW, 1,000-100,000) Chondroitin sulfate E GalNAc (4S,6S) GlcUA (MW, 1,000-100,000) Chondroitin sulfate K GalNAc (4S) GlcUA (3S) (MW, 1,000-100,000) Chondroitin polysulfate GalNAc (S) GlcUA (S) (MW, 1,000-150,000) Dermatan sulfate GalNAc (4S) IduUA, GlcUA (MW, 1,000-20,000) Heparin GlcNS (6S) GlcUA, IduUA (MW, 1,000-20,000) (2S) Heparan sulfate GlcNS (NAc,S) GlcUA, IduUA (MW, 1,000-20,000) (2S) Keratan sulfate GlcNAc (6S) Gal (MW, 1,000-20,000) Keratan polysulfate GlcNAc (6S) Gal (6S) (MW, 1,000-20,000) ______________________________________ GlcNAc: Nacetyl-D-glucosamine GalNAc: Nacetyl-D-galactosamine GlcNS: Dglucosamine Nsulfate GlcUA: Dglucuronic acid IduUA: Liduronic acid Gal: Dgalactose S: Osulfate
The phospholipid- or lipid-linked glycosaminoglycan of the present invention can be used as a salt, preferably with an alkali metal such as sodium, potassium or the like, an alkaline ea

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