USE OF NMR TO MEASURE TUMOR AND NORMAL TISSUE METAB DURING TUMOR ACIDIFICATION

使用 NMR 测量肿瘤酸化过程中肿瘤和正常组织的 Metab

• 批准号: 6300444
• 负责人: JERRY D GLICKSON
• 金额: $ 18.41万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6300444
• 关键词: Krebs' cycle; SCID mouse; acidity /alkalinity; aerobiosis; blood glucose; carbon; cellular pathology; cellular respiration; extracellular; glucose metabolism; glucose transport; glycolysis; human tissue; hyperglycemia; hyperthermia; intracellular; lactates; magnetic resonance imaging; melanoma; membrane transport proteins; neoplastic cell; nuclear magnetic resonance spectroscopy; stable isotope

This subcontract to Project 4 will examine metabolic and physiological aspects of acidification of human melanoma xenografts that are amenable to non-invasive measurement by magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI). These methods will be applied to animals supplied by Dr. Leeper's laboratory to test the hypothesis that NMR can non-invasively detect tumor specific changes in extracellular and intracellular pH (pHe and pHi, respectively) induced by hyperglycemia and by hyperglycemia plus inhibition of oxidative metabolism (with meta- iodobenzylguanidine, MiBG), and/or by hyperglycemia plus inhibition of the Na+/H+ cation exchanger (with Cariporide mesilate, HOE642) and the HCO3- /Cl-anion exchanger (with 4,4-diisothiocyanstilbene 2,2-disulphonic acid, DIDS). In addition, it is proposed that NMR can help delineate the underlying mechanism of acidification by hyperglycemia plus regulatory inhibition. To test this hypothesis, 31P MRS will be employed to measure the pHi and pHe in the tumor, in host muscle, and brain under conditions of normoglycemia, hyperglycemia plus MIBG and/or HOE642 plus DIDS. Inorganic phosphate (Pi) and 3-aminopropylphosphonate will serve as indicators of pHi and pHe, respectively. To test the hypothesis that tumor acidification under conditions of hyperglycemia and hyperglycemia plus respiratory inhibition is mediated by production of lactic acid (i.e., glycolysis), steady state lactate concentrations will be monitored on 1H MRS employing a selective multiple quantum coherence transfer pulse sequence developed by the subcontractor's laboratory to edit out the lactate resonance from interfering lipid resonances. Further insight into the mechanism of tumor acidification under conditions of hyperglycemia +/- respiratory inhibition will be obtained by measuring flux through the glycolytic pathway and through the TCA cycle from the kinetics of 13C-labeling of lactate and glutamate, respective, following infusion of [1-13C]glucose. The spatial distributions of 13C-labeled glucose and lactate in the tumor at isotope steady state (for glucose) will be imaged by 13C chemical shift imaging at constant concentrations of labeled glucose in the blood (19+/-) mM), and the vascular volume distribution will be imaged by dynamic 1H MRI using Gd-DTPA-albumin as a vascular marker. Images will be correlated with histology.

项目4的分包合同将检查代谢和生理 人类黑色素瘤异种移植物的酸化方面 磁共振光谱（MRS）和 磁共振成像（MRI）。这些方法将应用于动物 由Leeper博士的实验室提供，以检验NMR可以的假设 非侵入性检测细胞外肿瘤的特异性变化和 高血糖诱导的细胞内pH（分别 通过高血糖加上氧化代谢的抑制（具有元 碘苯甲胺，MIBG）和/或通过高血糖加上抑制 Na+/H+阳离子交换器（带有甲甲酸酯，HOE642）和HCO3-- /cl-anion交换器（具有4,4-二硫代氨基苯甲苯甲酸苯甲酸2,2-二异源酸， DID）。此外，建议NMR可以帮助描述 高血糖和调节性酸化的潜在机制 抑制。 为了检验该假设，将使用31p MRS来衡量PHI和 在肿瘤中的PHE，宿主肌肉和大脑 正常血糖，高血糖加上MIBG和/或HOE642 Plus Dids。无机 磷酸盐（PI）和3-氨基丙基膦酸酯将作为指标 Phi和Phe分别。测试肿瘤酸化的假设 在高血糖和高血糖的情况下 抑制是由乳酸的产生（即糖酵解）介导的 将在1H MRS上监测稳态乳酸浓度 选择性多量子相干传递脉冲序列开发了 由分包商的实验室编辑乳酸共振 干扰脂质共振。进一步了解肿瘤机制 高血糖+/-呼吸抑制条件下的酸化 将通过测量通过糖酵解途径的通量来获得 通过TCA周期从乳酸的13C标记和 在输注[1-13C]葡萄糖后，谷氨酸各自。空间 同位素的肿瘤中13C标记的葡萄糖和乳酸的分布 稳态（对于葡萄糖）将通过13C化学位移成像成像 血液中标记的葡萄糖的恒定浓度（19 +/-）mm）和 血管体积分布将通过使用动态1H MRI成像 GD-DTPA-Albumin作为血管标记。图像将与 组织学。