Depletion of glutathione in normal and malignant human cells in vivo by buthionine sulfoximine: clinical and biochemical results.
Depletion of glutathione in normal and malignant human cells in vivo by buthionine sulfoximine: clinical and biochemical results.
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丁硫氨酸亚磺酰亚胺体内正常和恶性人类细胞中谷胱甘肽的消耗：临床和生化结果。
DOI：
10.1093/jnci/84.4.264
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发表时间：
1992
期刊：
影响因子：
--
通讯作者：
Ozols,RF
中科院分区：
文献类型：
--
作者：
O'Dwyer,PJ;Hamilton,TC;Young,RC;LaCreta,FP;Carp,N;Tew,KD;Padavic,K;Comis,RL;Ozols,RF
在许多实验性肿瘤模型中，基于谷胱甘肽的解毒系统（由谷胱甘肽[GSH]和GSH相关酶、GSH转移酶和GSH过氧化物酶组成）的改变与对各种烷化剂、铂化合物和辐射的抗性相关（J）。Vistica等人(2J)证明了细胞谷胱甘肽含量与LI 210小鼠白血病细胞对美法仑耐药性的关系。GSH含量升高也是对美法仑和顺铂具有获得性或组成性抗性的人卵巢癌细胞系的重要特征（4-6）。在来自既往接受过治疗的患者的细胞系中发现GSH水平最高（NIH：OVCAR-3和NIH：OVCAR-4）（6）。对美法仑和顺铂具有体外诱导耐药性的其他细胞系（A 1847和A2780）的GSH水平比其来源的敏感细胞系高两倍至三倍（6）。在其他研究中，证明了美法仑耐药L1210细胞可以通过使用降低GSH含量的药物致敏（4，5）。用格里菲斯（7）合成的γ-谷氨酰半胱氨酸合成酶的特异性抑制剂L-丁硫酰亚砜亚胺（BSO）处理多种细胞系，可使烷化剂和铂化合物的IC 50降低2.4至6.0倍（5）。BSO的致敏作用已在荷瘤裸鼠体内得到证实（9）。虽然BSO确实增加了小鼠中美法仑的骨髓毒性，但其剂量调整效应远低于肿瘤组织中的剂量调整效应。因此，美法仑的治疗指数增加了3.6至6.5倍（10）。作为BSO临床评价的初步方法，我们用BSO治疗了9名患者（每12小时6次给药），然后在第5次BSO给药后给予烷化剂（美法仑）。给予最终BSO剂量以允许在GSH水平恢复之前形成链内和链间交联。为了分别评估该方案组分的毒性和生化作用，所有患者在第一疗程中单独接受BSO，一周后接受BSO和美法仑。我们在此报告了本研究初始部分的结果（正在进行中），以证明即使在本研究中测试的BSO初始剂量水平下，在正常和肿瘤组织中均观察到GSH耗竭。符合本研究条件的患者具有癌症的组织学诊断，
Alterations of the glutathione-based detoxification system (consisting of glutathione [GSH] and the GSH-related enzymes, GSH transferase, and GSH peroxidase) have been associated with resistance to various alkylating agents, platinum compounds, and radiation in many experimental tumor models (J). Vistica et al.(2J) demonstrated the relationship of cellular glutathione content and resistance to melphalan in LI210 murine leukemia cells. Elevated GSH content is also an important feature of human ovarian cancer cell lines with acquired or constitutive resistance to melphalan and cisplatin (4-6). The highest levels of GSH were found in cell lines derived from previously treated patients (NIH: OVCAR-3 and NIH: OVCAR-4)(6). Additional cell lines with induced in vitro resistance to melphalan and cisplatin (A 1847 and A2780) had a twofold to threefold higher level of GSH compared with that of the sensitive cell lines from which they were derived (6). In other studies, it was demonstrated that melphalan-resistant L1210 cells could be sensitized by the use of agents that lower GSH content (4, 5). Treatment of a variety of cell lines with L-buthionine sulfoximine (BSO), a specific inhibitor of y-glutamylcysteine synthetase synthesized by Griffith (7), decreases the IC50 for alkylating agents and platinum compounds by a factor of 2.4 to 6.0 (5). The sensitizing effects of BSO have been confirmed in vivo in tumor-bearing nude mice (9). While BSO did increase the myelotoxicity of melphalan in mice, the dose-modifying effect was considerably less than that in tumor tissue. As a result, the therapeutic index for melphalan was increased by a factor of 3.6 to 6.5 (10).As an initial approach to the clinical evaluation of BSO, we treated nine patients with BSO (every 12 hx 6 doses), followed by administration of the alkylator (melphalan) after the fifth BSO dose. The final BSO dose was administered to allow intrastrand and interstrand crosslinks to form before recovery of GSH levels. To assess separately the toxic and biochemical effects attributable to the components of this regimen, all patients received BSO alone in the first course, followed a week later by both BSO and melphalan. We report here the results of the initial portion of this study (which is in progress) to demonstrate that even at the initial dose level of BSO tested in this study, depletion of GSH is observed in both normal and tumor tissue. Patients eligible for this study had a histologic diagnosis of cancer and had