Growth inhibition of human melanoma tumor xenografts in athymic nude mice by swainsonine.
Swainsonine, an inhibitor of alpha-mannosidases, has been shown to block experimental metastasis of B16F10 melanoma and MDAY-D2 lymphoid tumor cells in syngeneic mice. In this report we demonstrate that swainsonine also reduces the growth rate of human melanoma cells in vitro and in vivo. Graded doses of swainsonine were administered either orally or via implanted Alzet miniosmotic pumps to athymic nude mice bearing subcutaneously implanted human MeWo melanoma cells. Swainsonine at 10 micrograms/ml in the drinking water or 0.5 mg/kg/day administered by miniosmotic pump reduced the growth rate of the MeWo tumors by approximately 50% and inhibited the expression of complex-type oligosaccharides in tumors and host intestine by only 10-20%. Swainsonine doses of 4 mg/kg/day reduced expression of complex-type oligosaccharides by 85% in vivo but afforded no additional inhibitory effect. A glycosylation mutant of MeWo called 3S5 has a defect in the synthesis of complex-type asparagine-linked oligosaccharides resulting in incomplete processing similar to that observed in swainsonine-treated MeWo tumor cells. Swainsonine did not inhibit the proliferation of 3S5 cells in vitro nor the growth of 3S5 tumors in nude mice. The results suggest that expression of highly branched complex-type oligosaccharides commonly associated with the malignant phenotype may provide the tumor cells with a growth advantage.
Dennis
J W
JW
Division of Cancer and Cell Biology, Mount Sinai Hospital Research Institute, Toronto, Ontario, Canada.
Koch
K
K
Yousefi
S
S
VanderElst
I
I
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002236:Carbohydrate Conformation; D002460:Cell Line; D006801:Humans; D008361:Mannosidases / Q000037:antagonists & inhibitors*; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D009844:Oligosaccharides / Q000378:metabolism; D017026:Swainsonine; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects
D000470:Alkaloids; D000970:Antineoplastic Agents; D009844:Oligosaccharides; D008361:Mannosidases; D017026:Swainsonine