Despite the major progresses in biomedical research and the development of novel therapeutics and treatment strategies, cancer is still among the dominant causes of death worldwide. One of the crucial challenges in the clinical management of cancer is primary (intrinsic) and secondary (acquired) resistance to both conventional and targeted chemotherapeutics. Multiple mechanisms have been identifiedthat underlie intrinsic and acquired chemoresistance: these include impaired drug uptake, increased drug efflux, deletion of receptors, altered drug metabolism, quantitative and qualitative alterations in drug targets, increased DNA damage repair and various mechanisms of anti-apoptosis. The fast efflux of anticancer drugs mediated by multidrug efflux pumps and the partial or complete reversibility of chemoresistance combined with the absence of genetic mutations suggests a multifactorial process. However, a growing body of recent evidence suggests that chemoresistance is often triggered by the highly acidic microenvironment of tumors. The vast majority of drugs, including conventional chemotherapeutics and more recent biological agents, are weak bases that are quickly protonated and neutralized in acidic environments, such as the extracellular microenvironment and the acidic organelles of tumor cells. It is therefore essential to develop new strategies to overcome the entrapment and neutralization of weak base drugs. One such strategy is the use of proton pump inhibitors which can enhance tumor chemosensitivity by increasing the pH of the tumor microenvironment. Recent clinical trials in animals with spontaneous tumors have indicated that patient alkalization is capable of reversing acquired chemoresistance in a large percentage of tumors that are refractory to chemotherapy. Of particular interest was the benefit of alkalization for patients undergoing metronomic regimens which are becoming more widely used in veterinary medicine. Overall, these results provide substantial new evidence that altering the acidic tumor microenvironment is an effective, well tolerated and low cost strategy for the overcoming of anticancer drug resistance.

中文翻译：

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微环境酸度是决定肿瘤化学耐药性的主要因素：质子泵抑制剂（PPI）是一种新颖的治疗方法。

尽管生物医学研究取得了重大进展，并且开发了新的疗法和治疗策略，但癌症仍然是全世界死亡的主要原因。癌症临床管理中的关键挑战之一是对常规化疗和靶向化疗的原发性（内在性）和继发性（获得性）抗性。已经确定了多种机制是内在和获得性化学抗性的基础：这些机制包括药物吸收受损，药物外排增加，受体缺失，药物代谢改变，药物靶标的数量和质量变化，DNA损伤修复和抗凋亡的各种机制。多药外排泵介导的抗癌药快速外排，化学抗性的部分或完全可逆性以及不存在基因突变的现象提示了一个多因素过程。但是，越来越多的最新证据表明，化学抗性通常是由肿瘤的高酸性微环境引发的。绝大多数药物，包括常规化学疗法和较新的生物制剂，都是弱碱，可在酸性环境（例如细胞外微环境和肿瘤细胞的酸性细胞器）中快速质子化和中和。因此，必须开发新的策略来克服弱碱药物的滞留和中和作用。一种这样的策略是使用质子泵抑制剂，其可以通过增加肿瘤微环境的pH来增强肿瘤化学敏感性。最近在具有自发性肿瘤的动物中进行的临床试验表明，患者的碱化能够逆转大部分难于化疗的肿瘤中获得的化学抗性。特别令人感兴趣的是碱化对于正在接受节律疗法的患者的益处，节律疗法正在越来越广泛地用于兽医学中。总体而言，这些结果提供了实质性的新证据，表明改变酸性肿瘤微环境是克服抗癌药耐药性的有效，耐受性良好且低成本的策略。最近在具有自发性肿瘤的动物中进行的临床试验表明，患者的碱化能够逆转大部分难于化疗的肿瘤中获得的化学抗性。特别令人感兴趣的是碱化对于正在接受节律疗法的患者的益处，节律疗法正在越来越广泛地用于兽医学中。总体而言，这些结果提供了实质性的新证据，表明改变酸性肿瘤微环境是克服抗癌药耐药性的有效，耐受性良好且低成本的策略。最近在具有自发性肿瘤的动物中进行的临床试验表明，患者的碱化能够逆转大部分难于化疗的肿瘤中获得的化学抗性。特别令人感兴趣的是碱化对于正在接受节律疗法的患者的益处，节律疗法正在越来越广泛地用于兽医学中。总体而言，这些结果提供了实质性的新证据，表明改变酸性肿瘤微环境是克服抗癌药耐药性的有效，耐受性良好且低成本的策略。特别令人感兴趣的是碱化对于正在接受节律疗法的患者的益处，节律疗法正在越来越广泛地用于兽医学中。总体而言，这些结果提供了实质性的新证据，表明改变酸性肿瘤微环境是克服抗癌药物耐药性的有效，耐受性良好且低成本的策略。特别令人感兴趣的是碱化对于正在接受节律疗法的患者的益处，节律疗法正在越来越广泛地用于兽医学中。总体而言，这些结果提供了实质性的新证据，表明改变酸性肿瘤微环境是克服抗癌药耐药性的有效，耐受性良好且低成本的策略。