New directions in cancer therapy based on aberrant expression of glycosphingolipids: anti-adhesion and ortho-signaling therapy.
Essentially all tumors express aberrantly glycosylated glycosphingolipids and glycoproteins, more commonly known as "tumor-associated carbohydrate antigens." In this article I propose two new forms of cancer therapy, anti-adhesion therapy and ortho-signaling therapy, which exploit these tumor-associated carbohydrates in distinct ways. The aim of anti-adhesion therapy is to disrupt the requisite carbohydrate-initiated interactions that occur between tumor cells and other cell types (e.g., endothelial cells, platelets) as tumors progress and metastasize. Candidate anti-adhesion agents include purified carbohydrates or glycosphingolipids representing H, Ley, sialosyl-Lex (or -Lea) GM3, or LacCer antigens, and monoclonal antibodies directed to these structures. The aim of ortho-signaling therapy is to disrupt mitogenic signaling pathways in tumor cells that are regulated by glycosphingolipids and/or their derivatives, including pathways involving receptor protein-kinases and protein kinase C. Candidate ortho-signaling agents are the glycosphingolipid regulator PDMP (1-phenyl-2-[decanoylamino]-3-morpholino-1-propanol) and the protein kinase C inhibitor DMS (N,N-dimethylsphingosine), both of which show antitumor activity in vitro and in animal studies.
Hakomori
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Biomembrane Institute, University of Washington, Seattle, Washington 98119.
D015295:Antigens, Tumor-Associated, Carbohydrate / Q000502:physiology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002240:Carbohydrate Sequence; D002448:Cell Adhesion / Q000187:drug effects*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D015195:Drug Design; D006028:Glycosphingolipids / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use; D006031:Glycosylation; D006801:Humans; D008081:Liposomes; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000556:secondary; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000502:physiology; D008954:Models, Biological; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D015398:Signal Transduction / Q000187:drug effects*
D015295:Antigens, Tumor-Associated, Carbohydrate; D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D006028:Glycosphingolipids; D008081:Liposomes; D008562:Membrane Glycoproteins