INHIBITORS OF CARBOHYDRATE PROCESSING - A NEW CLASS OF ANTICANCER AGENTS

There is a need for anticancer agents with novel mechanisms of action, Recently identified molecular targets for new anticancer agents inclu de inducers of cell differentiation, cell cycle arrest, and apoptosis, as well as signaling pathways for growth factors and cytokines. Anoth er unexplored opportunity is presented by the ubiquitous intracellular glycoprotein glycosylation pathway, This complex process, concerned w ith the addition of sugars onto newly synthesized proteins, occurs in the lumen of the rough endoplasmic reticulum and in the Golgi. There a re estimates of over 200 glycosyltransferase enzymes in this pathway, which results in considerable structural diversity of carbohydrates fo und on secreted and transmembrane glycoproteins, The specificity of gl ycosyltransferases for accepters and sugar-nucleotide donors dictates linkage positions between sugars, anomeric configuration of linkages, and monosaccharide composition, Specific carbohydrate structures parti cipate in cell-cell and cell-substratum interactions affecting process es such as lymphocyte trafficking, immune cell stimulation, embryogene sis, and cancer metastasis. Of the carbohydrate-processing inhibitors presently available, the alkaloid swainsonine, a Golgi or-mannosidase II inhibitor, is the first to have been selected for clinical testing based on its anticancer activity, p.o. availability, and low toxicity in mice, Herein, we review the rationale for targeting Golgi carbohydr ate processing pathways in the treatment of cancer, and summarize the preclinical and clinical results with swainsonine, Prospects for the d evelopment of second generation inhibitors with improved specificity f or Golgi-processing enzymes are discussed. Potential clinical applicat ions of this new class of anticancer agents are emphasized.