文章：

谷胱甘肽合成抑制剂丁硫氨酸亚砜胺协同增强了美法仑对多发性骨髓瘤临床前模型的活性

The glutathione synthesis inhibitor buthionine sulfoximine synergistically enhanced melphalan activity against preclinical models of multiple myeloma

原文发布日期：2014-07-18

DOI: 10.1038/bcj.2014.45

类型: Original Article

开放获取: 是

英文摘要：

Melphalan (L-PAM) has been an integral part of multiple myeloma (MM) treatment as a conditioning regimen before stem cell transplant (SCT). After initial response, most treated patients experience relapse with an aggressive phenotype. Increased glutathione (GSH) in MM may mediate resistance to L-PAM. We demonstrated that the GSH synthesis inhibitor buthionine sulfoximine (BSO) synergistically enhanced L-PAM activity (inducing 2–4 logs of cell kill) against nine MM cell lines (also in the presence of marrow stroma or cytokines) and in seven primary MM samples (combination indices <1.0). In MM cell lines, BSO significantly (P<0.05) depleted GSH, increased L-PAM-induced single-strand DNA breaks, mitochondrial depolarization, caspase cleavage and apoptosis. L-PAM depleted GSH, but GSH rapidly recovered in a L-PAM-resistant MM cell line unless also treated with BSO. Treatment with N-acetylcysteine antagonized BSO+L-PAM cytotoxicity without increasing GSH. In human MM xenografted into beige-nude-xid mice, BSO significantly depleted MM intracellular GSH and significantly increased apoptosis compared with L-PAM alone. BSO+L-PAM achieved complete responses (CRs) in three MM xenograft models including maintained CRs >100 days, and significantly increased the median event-free survival relative to L-PAM alone. Combining BSO with L-PAM warrants clinical testing in advanced MM.

摘要翻译： 

马法兰（L-PAM）作为干细胞移植（SCT）前的预处理方案，已成为多发性骨髓瘤（MM）治疗的重要组成部分。在初始治疗获得缓解后，多数患者会出现侵袭性表型的复发。MM中谷胱甘肽（GSH）的升高可能介导了对L-PAM的耐药性。我们证实GSH合成抑制剂丁硫氨酸-亚砜亚胺（BSO）能协同增强L-PAM对9个MM细胞系（在骨髓基质或细胞因子存在条件下亦然）及7个原代MM样本的杀伤活性（诱导2-4个数量级的细胞杀伤），联合指数均小于1.0。在MM细胞系中，BSO显著（P<0.05）降低GSH水平，增强L-PAM诱导的单链DNA断裂、线粒体去极化、 caspase裂解和细胞凋亡。L-PAM虽能消耗GSH，但在耐L-PAM的MM细胞系中GSH会快速恢复，除非同时使用BSO治疗。N-乙酰半胱氨酸处理可拮抗BSO+L-PAM的细胞毒性，且未增加GSH水平。在移植了人MM的beige-nude-xid小鼠模型中，与单用L-PAM相比，BSO显著降低MM细胞内GSH并显著增加细胞凋亡。在三种MM移植瘤模型中，BSO+L-PAM方案实现完全缓解（CR），其中持续缓解时间超过100天，且相较于单用L-PAM显著延长中位无事件生存期。BSO联合L-PAM方案值得在晚期MM中进行临床验证。

原文链接：

The glutathione synthesis inhibitor buthionine sulfoximine synergistically enhanced melphalan activity against preclinical models of multiple myeloma