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.

中文翻译：

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LS，R-丁硫氨酸亚砜亚胺：历史发展和临床问题。

LS，R-丁硫氨酸亚砜（LS，R BSO）是有效的γ-谷氨酰半胱氨酸合成酶的特异性抑制剂，是谷胱甘肽（GSH）生物合成中的限速步骤。基于强大的关联和最近的转染研究，GSH是肿瘤耐药性的重要组成部分。BSO对细胞内GSH的耗竭显着增强了许多细胞毒性剂（主要是烷基化剂和铂化合物）以及辐射和蒽环类化合物的细胞毒性。BSO + melphalan（L-PAM）的I期临床试验已经进行，仅BSO毒性很小，而BSO + L-PAM则增加了骨髓抑制。在连续测定（CI）BSO患者的肿瘤GSH水平的连续测定中，观察到GSH持续减少且一致（<对照组的10％）。在患有烷化剂或白化剂难治性肿瘤的患者中观察到临床活性的证据。L-PAM对CI BSO的第二阶段评估正在进行中。