L-S,R-buthionine sulfoximine: historical development and clinical issues.
L-S,R-buthionine sulfoximine (L-S,R BSO) is a potent specific inhibitor of gamma-glutamylcysteine synthetase, the rate-limiting step in glutathione (GSH) biosynthesis. GSH is an important component of tumor drug resistance based on a strong association and recent transfection studies. Depletion of intracellular GSH by BSO significantly enhances the cytotoxicity of many cytotoxic agents, principally alkylating agents and platinating compounds but also irradiation and anthracyclines. Phase I clinical trials of BSO + melphalan (L-PAM)have been carried out and observed little toxicity with BSO alone and increased myelosuppression with BSO + L-PAM. Consistent and profound (< 10% of control) GSH depletion was observed in serial determinations of tumor GSH levels in patients receiving continuous infusion (CI) BSO. Evidence of clinical activity has been observed in patients with alkylating or platinating agent-refractory tumors. Phase II evaluation of CI BSO with L-PAM is in progress.
Bailey
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University of Wisconsin Comprehensive Cancer Center, Department of Medicine, Madison 53792, USA. hhbailey@facstaff.wisc.edu
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000266:history / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019328:Buthionine Sulfoximine / Q000266:history* / Q000627:therapeutic use; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000266:history / Q000627:therapeutic use; D005260:Female; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors; D049673:History, 20th Century; D006801:Humans; D008297:Male; D008558:Melphalan / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D019328:Buthionine Sulfoximine; D005721:Glutamate-Cysteine Ligase; D008558:Melphalan