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Inhibition of L-Fucose Incorporation into Glycoprotein of Sarcoma 180 Ascites Cells by 6-Thioguanine¹

Department of Pharmacology and Developmental Therapeutics Program, Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06510

The incorporation of [³H]fucose into glycoproteins of Sarcoma 180 cells in vitro was decreased within 2 hr of exposure to 6-thioguanine (6-TG); 50% inhibition was produced by 8 µM 6-TG. Under identical conditions, no decrease in [³H]glucosamine incorporation into acid-insoluble material was detected. Similarly, [³H]fucose incorporation, but not [¹⁴C]glucosamine incorporation into glycoproteins of Sarcoma 180 ascites cells in vivo, was significantly reduced 1 to 6 hr after 6-TG treatment (20 mg/kg) of mice bearing 6-day implants of this neoplasm; the maximum depression of fucose utilization occurred at 2 hr after drug treatment. The decrease in [³H]fucose incorporation into glycoprotein was dose dependent and reached a maximum reduction of 77% of control incorporation 2 hr after 6-TG (10 mg/kg). The radioactivity from fucose found in acid-soluble extracts of Sarcoma 180 cells was decreased by 45% after 6-TG (10 mg/kg). In contrast, this concentration of 6-TG did not decrease the level of radioactivity from [³H]fucose found in acid-soluble extracts of a subline of Sarcoma 180 resistant to 6-TG and produced only a 38% decrease in fucose incorporation into the acid-insoluble fraction of this neoplasm. The inhibition of [³H]fucose incorporation into glycoproteins of Sarcoma 180 produced by 6-TG appeared to be due to a drug-induced decrease in the formation of guanosine diphosphate-[³H]fucose and a concomitant decrease in the intracellular content of guanosine diphosphate-fucose. These data suggest that 6-TG exerts, as a metabolic lesion, a suppression of guanine nucleotide sugar biosynthesis. Since fucose is largely a terminal carbohydrate of glycoproteins and glycolipids of the plasma membrane, 6-TG may alter membrane composition. This phenomenon may be associated with the cytotoxicity of 6-TG to neoplastic cells.

¹ Supported in part by Grants CA-02817 and CA-16359 from the National Cancer Institute, USPHS.

² Present address: Section of Immunology, Department of Developmental Therapeutics, M. D. Anderson Hospital, University of Texas System Cancer Center, Houston, Tex. 77025.

Received 2/ 7/77. Accepted 8/23/77.