Colorectal metastases is facilitated by specific alterations in tumor cell surface molecules involved in cellular recognition and adhesion. Genetic changes (loss of DCC, deleted in colorectal cancer, gene) leading to the deletion of neural cell adhesion-like molecule (NCAM) have been observed in colorectal cancer progression. Furthermore, overexpression of other colorectal carcinoma glycoproteins (e.g. CEA) implicated in adhesive interactions has been found to be associated with increased metastatic potential. Together these findings raise considerable interest in colorectal tumor cell surface glycoproteins and glycolipids, an the role these molecules play in tumor cell adhesion, recognition, growth and invasion. To target CEA and other colon tumor cell surface glycoconjugates, 3- and 4-fluorinated derivatives of glucosamine (e.g. 4-F- GlcNAc) were synthesized by our group as potential oligosaccharide chain terminators and/or modifiers. By substitution of fluorine into the C3 or C4 position, these analogs were designed to block the biosynthesis of Galpha1beta1 yields 4 GlcNAc and Fuc alpha1 yields 3 GlcNac oligosaccharide linkages, important constituents of polylactosaminoglycans and various antigenic blood groupings, including sialylated lewis X.
The aim of this proposal is to evaluate the biochemical, biological and preclinical therapeutic activities of these fluoro-sugars, and several other newly synthesized monosaccharide analogs and oligosaccharides, using various human colon carcinoma cell lines and tumor models. Preliminary studies have indicated that treatment of HT-29 human colon carcinoma cells with a 4-F-GlcNAc analog resulted in decreased expression of certain cell surface glycoconjugates (e.g. CEA) correlating with decreased homotypic aggregation. Additionally, following exposure of these cells to this sugar analog, reductions in HT-29 cell surface sialylated Lewis X reactivity were noted with corresponding decreases in adhesion to IL-1beta stimulated endothelial cells (an E-selectin mediated adhesion system). Such losses in surface glycoconjugate expression and cell-to-cell adhesiveness may result in an inability for such tumor cells to metastasize. Using magnetic resonance imaging (MRI), we propose to monitor the advent of liver metastases (from intrasplenic and/or orthotopic tumor implants) in nude athymic (or SCID) mice, and to assess the preclinical therapeutic efficacy of anti-adhesive therapies. it is anticipated that these studies will increase our knowledge concerning mechanisms of colon tumor cell adhesion, invasion, growth regulation and metastases, perhaps leading to the discovery and development of new and unique agents having antitumor and/or antimetastatic activity.
