Antitumor Activities Of 2-Fluorofucose, An Orally Active Agent That Inhibits Cell-Surface Fucosylation

Fucose is a component of many carbohydrates that are found on the outer membranes of cancer cells. There is evidence that loss of this sugar from cell-surface glycoproteins can change cancer cell behavior, including growth and metastasis. We have previously demonstrated that 2-fluorofucose (SGD-2083) blocks the fucosylation of antibodies in vitro and in vivo due to the depletion of GDP-activated fucose inside cells. These findings provide the basis for evaluating the antitumor activities of SGD-2083, since alterations of the fucose content on cell surfaces could potentially impact tumor growth and adhesion. To explore this, SGD-2083 was given orally to mice with carcinoma and hematologic tumor xenografts. Significant antitumor activities were obtained in prostate, renal cell and colorectal carcinomas, but not in the two hematologic cancer models tested. The doses used to achieve efficacy were well-tolerated. FACS analysis was used to detect alterations in tumor cell surface fucosylation in animals that responded to treatment with SGD-2083. Signal reduction was observed on E-selectin ligand and several other cell surface fucose linkages, while little or no response to the treatment was observed in the fucosylation of cell surface P-selectin ligand. These results show that oral administration of SGD-2083 leads to the alteration of tumor cell surface fucosylation in a well-defined manner, and this may account for the observed activities of this novel antitumor agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2945. doi:1538-7445.AM2012-2945