Bailey H H
University of Wisconsin Comprehensive Cancer Center, Department of Medicine, Madison 53792, USA.
Chem Biol Interact. 1998 Apr 24;111-112:239-54. doi: 10.1016/s0009-2797(97)00164-6.
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.
L-S，R-丁硫氨酸亚砜胺（L-S，R BSO）是γ-谷氨酰半胱氨酸合成酶的一种强效特异性抑制剂，而γ-谷氨酰半胱氨酸合成酶是谷胱甘肽（GSH）生物合成中的限速步骤。基于密切关联和近期的转染研究，GSH是肿瘤耐药性的一个重要组成部分。BSO使细胞内GSH耗竭可显著增强许多细胞毒性药物的细胞毒性，主要是烷化剂和铂类化合物，也包括辐射和蒽环类药物。已经开展了BSO + 美法仑（L-PAM）的I期临床试验，结果显示单独使用BSO时毒性较小，而BSO + L-PAM会增加骨髓抑制。在接受持续输注（CI）BSO的患者中，连续测定肿瘤GSH水平时观察到一致且显著（<对照的10%）的GSH耗竭。在患有烷化剂或铂类药物难治性肿瘤的患者中已观察到临床活性的证据。CI BSO与L-PAM的II期评估正在进行中。
