Abstract
The glutathione synthase inhibitor, buthionine sulfoximine (BSO), specifically enhances the cytotoxic effects of treosulfan in human glioma cells. BSO depletes glutathione and greatly enhances treosulfan cytotoxicity in all the 12 human malignant glioma cell lines examined. None of these cell lines showed enhanced susceptibility to CD95L- or tumor necrosis factor (TNF)-alpha-induced apoptosis when glutathione is depleted. The combination of serial systemic BSO applications (300 mg/kg) and a single systemic dose of treosulfan (2.5 g/kg) reduced the growth of intracranially growing rat C6 gliomas in vivo by 73% whereas treosulfan alone reduced tumor growth by 16% and BSO alone had no effect. BSO lowered glutathione levels to 25-30% in peripheral blood mononuclear cells (PBMC) and to 50% in the glioma tissue. The glutathione levels in the non-tumor-bearing contralateral hemisphere were unaffected by systemic BSO treatment. The main side effects of treosulfan, gastrointestinal and bone marrow toxicity, were not significantly enhanced by BSO.
MeSH terms
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Animals
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Antimetabolites, Antineoplastic / toxicity*
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Antineoplastic Agents, Alkylating / toxicity*
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Apoptosis / drug effects
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Blood Cell Count
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Brain Neoplasms / drug therapy*
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Brain Neoplasms / genetics
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Brain Neoplasms / pathology
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Busulfan / analogs & derivatives*
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Busulfan / toxicity*
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Buthionine Sulfoximine / toxicity*
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Cell Division / drug effects
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Drug Synergism
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Fas Ligand Protein
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Gene Transfer Techniques
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Glioma / drug therapy*
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Glioma / genetics
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Glioma / pathology
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Glutathione / metabolism
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Humans
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In Vitro Techniques
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Ligands
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Membrane Glycoproteins / pharmacology*
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Neoplasm Transplantation
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Rats
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Rats, Sprague-Dawley
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Survival Rate
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / metabolism
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Tumor Necrosis Factor-alpha / pharmacology
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fas Receptor / pharmacology*
Substances
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Antimetabolites, Antineoplastic
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Antineoplastic Agents, Alkylating
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FASLG protein, human
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Fas Ligand Protein
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Faslg protein, rat
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Ligands
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Membrane Glycoproteins
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Tumor Necrosis Factor-alpha
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fas Receptor
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Buthionine Sulfoximine
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treosulfan
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Busulfan
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Glutathione