L-S,R-buthionine sulfoximine:: historical development and clinical issues
L-S,R-buthionine sulfoximine:: historical development and clinical issues
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DOI：
10.1016/s0009-2797(97)00164-6
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发表时间：
1998-04-24
影响因子：
5.1
通讯作者：
Bailey, HH
中科院分区：
文献类型：
--
作者：
Bailey, HH
L S，R BSO（L-S，R BSO）是谷氨酰半胱氨酸合成酶（GSH）的一个限速步骤，是谷氨酰半胱氨酸合成酶的特异性抑制剂。基于强关联和最近的转染研究，GSH是肿瘤耐药的重要组成部分。BSO对细胞内GSH的消耗显著增强了许多细胞毒性剂的细胞毒性，主要是烷化剂和铂化合物，但也包括辐射和蒽环类药物。已经进行了BSO +美法仑（L-PAM）的I期临床试验，并且观察到单独使用BSO的毒性很小，而使用BSO + L-PAM的骨髓抑制增加。在接受连续输注（CI）BSO的患者中，在肿瘤GSH水平的系列测定中观察到一致和深刻的（<对照的10%）GSH耗竭。在烷化剂或铂剂难治性肿瘤患者中观察到临床活性证据。使用L-PAM的CI BSO的II期评价正在进行中。(C)1998由Elsevier Science爱尔兰有限公司出版。保留所有权利。
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. (C) 1998 Published by Elsevier Science Ireland Ltd. All rights reserved.