Targeting the Tumor pH Gradient for the Treatment of Ca.

靶向肿瘤 pH 梯度治疗 Ca。

• 批准号: 6757887
• 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/6757887
• 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）：使用申请31p-ragnetic共振光谱在生物组织中，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也有所不同。这项研究的总体目的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，体外研究证实，细胞pH梯度明显影响表现出弱酸性或碱性特性的药物的细胞内分布。这一发现的临床相关性是深远的。对已发表数据的分析表明，人类的肿瘤和正常组织之间的细胞pH梯度显着不同，此外，这种差异的幅度随着供应血管的径向距离的增加而增加。这项研究确定pH梯度是否控制了复杂和动态肿瘤微环境中弱电解质的细胞毒性，因此是否可以利用肿瘤和正常组织之间的pH梯度差异来治疗癌症。为了评估这一假设，在正常和pH梯度修饰的条件下，弱酸化学治疗诱导的肿瘤生长延迟将与弱碱基诱导的肿瘤生长延迟进行比较。如果pH梯度依赖性假设是可操作的体内，则pH梯度变化将对这两个弱电解质的细胞毒性产生相反的影响。其次，将评估pH梯度修饰后肿瘤生长延迟的大小，将评估带有两个电离基团的电解质。如果有效，则pH梯度依赖性药物的摄取将导致两个电解质的肿瘤生长延迟变化。第三个目标确定pH梯度修饰是否影响功能性脉管系统最远端的肿瘤细胞中的药物细胞毒性，并且该作用的大小是否大于或小于与功能脉管系统更近端的细胞。重要的是，比较弱酸与基础的影响将排除掩盖或模仿任何pH梯度效应，其次是诱导的肿瘤血流变化或对肿瘤微环境的结果作用。确认本应用中提出的假设将为肿瘤组织的细胞内区室的设计和利用提供基础，包括供应血管远端的肿瘤区域，这些肿瘤区域供应血管，这些肿瘤区域暴露于最低的系统施用药物浓度，并且可能越来越多地辐射辐射射击。