Department of Radiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, United States.
Mol Pharm. 2011 Dec 5;8(6):2032-8. doi: 10.1021/mp200292c. Epub 2011 Oct 26.
Despite advances in developing novel therapeutic strategies, a major factor underlying cancer related death remains resistance to therapy. In addition to biochemical resistance, mediated by xenobiotic transporters or binding site mutations, resistance can be physiological, emerging as a consequence of the tumor's physical microenvironment. This review focuses on extracellular acidosis, an end result of high glycolytic flux and poor vascular perfusion. Low extracellular pH, pHe, forms a physiological drug barrier described by an "ion trapping" phenomenon. We describe how the acid-outside plasmalemmal pH gradient negatively impacts drug efficacy of weak base chemotherapies but is better suited for weakly acidic therapeutics. We will also explore the physiologic changes tumor cells undergo in response to extracellular acidosis which contribute to drug resistance including reduced apoptotic potential, genetic alterations, and elevated activity of a multidrug transporter, p-glycoprotein, pGP. Since low pHe is a hallmark of solid tumors, therapeutic strategies designed to overcome or exploit this condition can be developed.
尽管在开发新的治疗策略方面取得了进展，但癌症相关死亡的一个主要因素仍然是对治疗的耐药性。除了由外源性转运体或结合部位突变介导的生化耐药性外，耐药性还可以是生理性的，是肿瘤物理微环境的结果。这篇综述重点介绍细胞外酸中毒，这是高糖酵解通量和血管灌注不良的最终结果。低细胞外 pH 值，pHe，形成了一种“离子捕获”现象描述的生理药物屏障。我们描述了质膜外 pH 梯度的酸外侧如何对弱碱性化学疗法的药物疗效产生负面影响，但更适合弱酸性治疗药物。我们还将探讨肿瘤细胞对细胞外酸中毒的生理反应，这些反应有助于产生耐药性，包括凋亡潜力降低、遗传改变和多药转运蛋白 p-糖蛋白（pGP）活性升高。由于低 pHe 是实体瘤的标志，可以开发旨在克服或利用这种情况的治疗策略。
