Targeting Tumor pH Gradient for the Treatment of Cancer

靶向肿瘤 pH 梯度治疗癌症

• 批准号: 6677937
• 负责人: LEO E GERWECK
• 金额: $ 20.47万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-10 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6677937
• 关键词: acid base balance; acidity /alkalinity; acids; athymic mouse; base; blood glucose; cytotoxicity; doxorubicin; drug delivery systems; electrolytes; extracellular; flow cytometry; high performance liquid chromatography; intracellular; male; mitoxantrone; neoplasm /cancer blood supply; neoplasm /cancer chemotherapy; pharmacokinetics

DESCRIPTION (provided by applicant): With the application 31P-magnetic resonance spectroscopy to living tissue, it has been established that the cellular pH of tumors and of normal tissue is similar, whereas the extracellular pH differs between these tissues. The overall objective of this research is to exploit the resulting difference in the cellular pH gradient between tumor and normal tissue, for the treatment of cancer. Theory predicts, and in-vitro studies confirm, that the cell pH gradient markedly influences the intra-extracellular distribution of drugs exhibiting weak acidic or basic properties. The clinical relevance of this finding is profound. Analysis of published data reveals that the cell pH gradient substantially differs between tumor and normal tissue in humans, and additionally, the magnitude of this difference increases with increasing radial distance from supplying vessels. This study determines if the pH gradient governs the cytotoxicity of weak electrolytes in the complex and dynamic tumor microenvironment, and therefore whether the pH gradient difference between tumor and normal tissue can be exploited for the treatment of cancer. To evaluate this hypothesis, tumor growth delay induced by a weak acid chemotherapeutic will be compared to that induced by a weak base, under normal and pH gradient modified conditions. If the pH gradient dependent hypothesis is operative in-vivo, a pH gradient change will have opposite effects on the cytotoxicity of these two weak electrolytes. Second, the magnitude of tumor growth delay following pH gradient modification will be evaluated for electrolytes bearing two vs one ionizable group. If operative, pH gradient dependent drug uptake will lead to substantially different tumor growth delay changes for the two electrolytes. A third aim determines if pH gradient modification influences drug cytotoxicity in tumor cells most distal from functional vasculature, and if the magnitude of this effect is greater or less than pertains to cells more proximal to functional vasculature. Importantly, comparing the effects of a weak acid vs base, will preclude the masking or mimicking of any pH gradient effect, secondary to induced changes in tumor blood flow or resulting consequential effects on the tumor microenvironment. Confirmation of the hypothesis proposed in this application will provide a basis for the design and utilization of drugs which preferentially accumulate in the intracellular compartment of tumor tissue, including those tumor regions distal from supplying vessels, which are exposed to the lowest concentration of systemically administered drugs, and which are likely to be increasingly radioresistant.

描述（由申请人提供）：通过将31P-磁共振波谱应用于活体组织，已经确定肿瘤和正常组织的细胞pH值相似，而这些组织之间的细胞外pH值不同。这项研究的总体目标是利用肿瘤和正常组织之间细胞 pH 梯度的差异来治疗癌症。理论预测并且体外研究证实，细胞 pH 梯度显着影响弱酸性或碱性药物的细胞内分布。这一发现的临床意义是深远的。对已发表数据的分析表明，人类肿瘤组织和正常组织之间的细胞 pH 梯度存在显着差异，而且这种差异的幅度随着距供应血管的径向距离的增加而增加。这项研究确定了复杂且动态的肿瘤微环境中pH梯度是否控制弱电解质的细胞毒性，从而确定肿瘤和正常组织之间的pH梯度差异是否可以用于癌症的治疗。为了评估这一假设，将在正常和 pH 梯度修改条件下，将弱酸化疗诱导的肿瘤生长延迟与弱碱诱导的肿瘤生长延迟进行比较。如果 pH 梯度依赖假说在体内有效，则 pH 梯度变化将对这两种弱电解质的细胞毒性产生相反的影响。其次，将评估具有两种与一种可电离基团的电解质在pH梯度改变后肿瘤生长延迟的程度。如果有效，pH 梯度依赖性药物摄取将导致两种电解质的肿瘤生长延迟变化显着不同。第三个目标是确定 pH 梯度修改是否会影响距离功能性脉管系统最远的肿瘤细胞中的药物细胞毒性，以及这种影响的程度是否大于或小于距离功能性脉管系统较近的细胞。重要的是，比较弱酸与碱的影响，将排除任何 pH 梯度效应的掩蔽或模仿，这种效应继发于肿瘤血流的诱导变化或对肿瘤微环境产生的间接影响。本申请中提出的假设的证实将为优先积聚在肿瘤组织的细胞内区室中的药物的设计和利用提供基础，所述肿瘤组织包括远离供应血管的那些暴露于最低浓度的全身施用药物的肿瘤区域，并且它们的抗辐射能力可能会越来越强。