Potential for selective modulation of glutathione in cancer chemotherapy
Potential for selective modulation of glutathione in cancer chemotherapy
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DOI：
10.1016/s0009-2797(97)00166-x
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发表时间：
1998-04-24
影响因子：
5.1
通讯作者：
Batist, G
中科院分区：
文献类型：
--
作者：
Chen, X;Carystinos, GD;Batist, G
尽管在抗癌疗法开发方面正在取得进展，但持续存在的问题仍然是选择性靶向肿瘤，同时保留正常组织。这在很大程度上是混淆的，因为正常细胞和肿瘤细胞之间的差异通常是微妙的，并且是梯度的一部分，其中与宿主正常组织相比，基因产物可能在肿瘤中或多或少地表达，但很少在肿瘤中表达（或关闭）。谷胱甘肽（GSH）和相关酶在细胞对外源性物质（包括化疗）的耐药性中的作用已得到充分证实。这项研究是试图调节GSH以获得治疗优势的研究之一。作者简要描述了γ-谷氨酰半胱氨酸合成酶抑制剂丁硫酰亚胺的经验，然后更详细地概述了使用半胱氨酸前药L-2-氧代噻唑烷-4-羧酸酯的潜在更具选择性的方法的最新证据。这导致了对活化酶5-氧代-L-脯氨酸酶的详细研究，包括酶和免疫表征，以及其调节剂对抗癌药物毒性的影响的体外研究。使用高亲和力抗体，作者已经产生了关于这种酶在肿瘤和正常人体组织中分布的有趣信息。最后，作者一直在研究调节间隙连接作为抗癌治疗的一部分的潜力，因为它们在细胞之间转运GSH，并且通常在肿瘤细胞中缺乏。初步研究表明，缝隙连接诱导可能会显着耗尽GSH浓度的肿瘤细胞和敏感的各种治疗。(C)1998爱思唯尔科学爱尔兰有限公司保留所有权利。
Notwithstanding ongoing progress in anticancer therapeutics development, the persistent problem remains to selectively target tumors while sparing normal tissues. This is confounding largely because the differences between normal and tumor cells are often subtle and part of a gradient, where a gene product may be more or less expressed in tumor compared with the host normal tissue, but seldom expressed (or turned off) in tumors. The role of glutathione (GSH) and related enzymes in cellular resistance to xenobiotics, including chemotherapy is well established. This study is among those attempting to modulate GSH to therapeutic advantage. The authors briefly describe the experience with the gamma-glutamylcysteine synthetase inhibitor buthionine sulfoximine, and then in greater detail outline recent evidence for a potentially more selective approach using the cysteine prodrug L-2-oxothiazolidine-4-carboxylate . This has led to a detailed study of the activating enzyme 5-oxo-L-prolinase, including enzymatic and immunocharacterization, as well as in vitro study of the effect of its modulators on anticancer drug toxicity. Using high affinity antibodies the authors have generated interesting information on the distribution of this enzyme in tumor versus normal human tissues. Finally, the authors have been studying the potential for modulating gap junctions as a part of anti-cancer therapeutics, since they transport GSH between cells and are generally deficient in tumor cells. Preliminary studies suggest that gap junction induction may dramatically deplete GSH concentration in tumor cells and sensitize them to a variety of treatments. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.