Reber U, Wüllner U, Trepel M, Baumgart J, Seyfried J, Klockgether T, Dichgans J, Weller M
Department of Neurology, University of Tübingen, School of Medicine, Germany.
Biochem Pharmacol. 1998 Feb 1;55(3):349-59. doi: 10.1016/s0006-2952(97)00480-2.
Median survival of human malignant glioma patients is less than one year even with cytoreductive surgery and postoperative radiotherapy. Adjuvant chemotherapy has been rather ineffective. Here, we studied the potentiation by L-buthionine-[S,R]-sulfoximine (BSO), a glutathione-depleting agent, of anticancer drug actions on two human malignant glioma cell lines, LN-229 and T98G. LN-229 has wild-type p53 status, T98G is mutant for p53. Glutathione levels were depleted by BSO with similar kinetics in both cell lines. Only LN-229 cells were growth-inhibited by BSO. BSO had minor effects on the toxicity of doxorubicin, ACNU (1-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-3-(2-chloroethyl)-3-nitrosou rea, nimustine) and vincristine. BSO failed to alter teniposide or cytarabine toxicity. BSO induced prominent sensitization to the alkylating agent, treosulfan, in both cell lines, as assessed by viability assays, in situ DNA end labeling and quantitative DNA fragmentation. Treosulfan is thought to mediate toxicity via formation of reactive epoxides. In the absence of BSO, treosulfan had little acute cytotoxic and moderate antiproliferative effects. Synergistic glioma cell cytotoxicity induced by treosulfan and BSO was not associated with reactive oxygen species formation. Ectopic expression of bcl-2 did not alter basal glutathione levels but attenuated glutathione depletion induced by BSO. Bcl-2 provided only moderate protection from synergistic induction of glioma cell death by treosulfan and BSO. Glutathione depletion may play a role in BSO-mediated chemosensitization, but other mechanisms are probably involved as well. BSO may be a useful agent for glioma cell sensitization to specific chemotherapeutic drugs such as treosulfan.
即使进行了减瘤手术和术后放疗，人类恶性胶质瘤患者的中位生存期仍不足一年。辅助化疗效果一直不佳。在此，我们研究了谷胱甘肽耗竭剂L-丁硫氨酸-[S,R]-亚砜亚胺（BSO）对两种人类恶性胶质瘤细胞系LN-229和T98G的抗癌药物作用的增强作用。LN-229具有野生型p53状态，T98G的p53为突变型。在两种细胞系中，BSO以相似的动力学耗尽谷胱甘肽水平。只有LN-229细胞受到BSO的生长抑制。BSO对阿霉素、ACNU（1-[(4-氨基-2-甲基-5-嘧啶基)甲基]-3-(2-氯乙基)-3-亚硝基脲，尼莫司汀）和长春新碱的毒性影响较小。BSO未能改变替尼泊苷或阿糖胞苷的毒性。通过活力测定、原位DNA末端标记和定量DNA片段化评估，BSO在两种细胞系中均诱导对烷化剂苏消安的显著敏感性。苏消安被认为通过形成反应性环氧化物来介导毒性。在没有BSO的情况下，苏消安几乎没有急性细胞毒性和中度抗增殖作用。苏消安和BSO诱导的协同胶质瘤细胞毒性与活性氧的形成无关。bcl-2的异位表达未改变基础谷胱甘肽水平，但减弱了BSO诱导的谷胱甘肽耗竭。Bcl-2仅对苏消安和BSO协同诱导的胶质瘤细胞死亡提供适度保护。谷胱甘肽耗竭可能在BSO介导的化学增敏中起作用，但可能也涉及其他机制。BSO可能是一种有用的药物，可使胶质瘤细胞对诸如苏消安等特定化疗药物敏感。
