Melanoma cytotoxicity of buthionine sulfoximine (BSO) alone and in combination with 3,4-dihydroxybenzylamine and melphalan.
Buthionine sulfoximine (BSO), a specific inhibitor of glutathione synthesis, showed variable growth-inhibitory activity in different tumor cell lines with a high degree of inhibitory activity against melanoma-derived cell lines. A correlation between BSO growth-inhibitory effects and cellular glutathione peroxidase activity was observed. In contrast, no correlation was demonstrated between the response to BSO and cellular tyrosinase, gamma-glutamylcysteine synthetase, glutathione transferase, gamma-glutamyl transpeptidase, or glutathione reductase activities. BSO enhanced 3,4-dihydroxybenzylamine (3,4-DHBA) (fourfold) and melphalan (threefold) in vitro cytotoxic activity as determined by inhibition of DNA synthesis in human melanoma cells and this enhancement was dependent on the duration of exposure to drug. BSO demonstrated in vivo antitumor activity in B16 melanoma-bearing mice prolonging survival by 29% and in combination with 3,4-DHBA resulted in a slight (48% versus 38%) increase in life span as compared to 3,4-DHBA alone. The combination of BSO and melphalan, however, increased the life span of B16 melanoma-bearing mice by 170%, as compared to melphalan alone (80%). These studies demonstrate a unique in vivo antimelanoma activity of BSO.
Prezioso
J A
JA
Laboratory of Molecular Dermatologic Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
FitzGerald
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GB
Wick
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MM
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D019328:Buthionine Sulfoximine; D004298:Dopamine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D005979:Glutathione Peroxidase / Q000032:analysis; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy; D008558:Melphalan / Q000008:administration & dosage*; D008717:Methionine Sulfoximine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D014407:Tumor Cells, Cultured
D008717:Methionine Sulfoximine; C022133:3,4-dihydroxybenzylamine; D019328:Buthionine Sulfoximine; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D008558:Melphalan; D004298:Dopamine