Inhibition of L-fucose incorporation into glycoprotein of Sarcoma 180 ascites cells by 6-thioguanine.

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 pro duced by 8 /nM 6-TG. Under identical conditions, no de crease 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 resist ant to 6-TG and produced only a 38% decrease in fucose incorporation into the acid-insoluble fraction of this neo plasm. The inhibition of [3H]fucose incorporation into gly coproteins 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 de crease 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 car bohydrate of glycoproteins and glycolipids of the plasma membrane, 6-TG may alter membrane composition. This phenomenon may be associated with the cytotoxicity of 6TG to neoplastic cells.