Tumor acidity, ion trapping and chemotherapeutics I.: Acid pH affects the distribution of chemotherapeutic agents in vitro
Tumor acidity, ion trapping and chemotherapeutics I.: Acid pH affects the distribution of chemotherapeutic agents in vitro
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DOI：
10.1016/s0006-2952(03)00467-2
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发表时间：
2003-10-01
影响因子：
5.8
通讯作者：
Gillies, RJ
中科院分区：
文献类型：
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作者：
Mahoney, BP;Raghunand, N;Gillies, RJ
对抗癌化疗的耐药性通常会导致局部衰竭，并且可能是由生化和/或生理机制引起的。生化机制包括赋予抗性的蛋白质的过度表达。相反，生理抵抗涉及肿瘤微环境，并且可能由灌注不良、缺氧和/或酸性引起。本次通讯研究了肿瘤酸度在对一组常用于治疗乳腺癌的化疗药物（例如蒽环类药物、紫杉烷类药物、抗代谢药物和烷化剂）的耐药性中的作用。确定了 pH 对这些药物细胞毒性的影响，并通过监测 pH 对放射性标记蒽环类药物细胞摄取的影响来证实离子捕获。此外，还比较了亲代药物敏感的 MCF-7 细胞与过表达 p-糖蛋白 (MDR-1) 和乳腺癌抗性蛋白的变体之间的 pH 依赖性细胞毒性和摄取。这些数据表明，pH 依赖性离子捕获产生的生理抗性的程度与药物外排泵过度表达引起的生化抗性相当。因此，基于微环境的离子捕获是基于蒽环类化疗的重要障碍，并且本身可以成为增强现有化疗疗效的治疗靶点。 (C) 2003 Elsevier Inc. 保留所有权利。
Resistance to anti-cancer chemotherapies often leads to regional failure, and can be caused by biochemical and/or physiological mechanisms. Biochemical mechanisms include the overexpression of resistance-conferring proteins. In contrast, physiological resistance involves the tumor microenvironment, and can be caused by poor perfusion, hypoxia and/or acidity. This communication investigates the role of tumor acidity in resistance to a panel of chemotherapeutic agents commonly used against breast cancer, such as anthracyclines, taxanes, anti-metabolites and alkylating agents. The effects of pH on the cytotoxicity of these agents were determined, and ion trapping was confirmed by monitoring the effect of pH on the cellular uptake of radiolabeled anthracyclines. Furthermore, pH-dependent cytotoxicity and uptake were compared between parental drug sensitive MCF-7 cells and variants overexpressing p-glycoprotein (MDR-1) and Breast Cancer Resistance Protein. These data indicate that the magnitude of physiological resistance from pH-dependent ion trapping is comparable to biochemical resistance caused by overexpression of drug efflux pumps. Hence, microenvironment-based ion trapping is a significant barrier to anthracycline-based chemotherapy and can itself be a therapeutic target to enhance the efficacy of existing chemotherapies. (C) 2003 Elsevier Inc. All rights reserved.