NMR of Melanoma Acidification, Bioenergetics, Metabolism and Therapeutic Response

黑色素瘤酸化、生物能量学、代谢和治疗反应的 NMR

• 批准号: 7847669
• 负责人: JERRY D GLICKSON
• 金额: $ 46.69万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-21 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7847669
• 关键词: 4-coumaric acid; Acute; Adrenal Glands; Affect; Alkylating Agents; Antineoplastic Agents; Bioenergetics; Biological Assay; Blood Vessels; Bone Marrow; Brain; Canada; Canis familiaris; Cisplatin; Clinic; Clinical; Clinical Trials; Cyclophosphamide; Data; Development; Disease; Dose; Dose-Limiting; Drug Administration Routes; Drug Kinetics; Drug Sensitization; Electron Transport; Energy-Generating Resources; Enzymes; Europe; Event; Excision; Exhibits; FDA approved; Fever; Glioma; Glucose; Glycolysis; Goals; Grant; Heart; Histopathology; Human; Hyperglycemia; Infusion procedures; Kidney; Laboratories; Lactic acid; Life; Liver; Lonidamine; Magnetic Resonance Imaging; Malignant Neoplasms; Mammary Neoplasms; Maximum Tolerated Dose; Measurement; Mechlorethamine; Melphalan; Metabolic; Metabolism; Methods; Mitochondria; Modeling; Monocarboxylic Acid Transporters; Mus; Muscle; Myalgia; NHE1; Neoplasm Metastasis; Normal Cell; Normal tissue morphology; Nude Mice; Omeprazole; Operative Surgical Procedures; Optics; Oral; Oral Administration; Oxidation-Reduction; Oxidative Phosphorylation; Pain; Pathway interactions; Procedures; Production; Protein Isoforms; Protocols documentation; Proton Pump Inhibitors; Proton-Translocating ATPases; Pump; Pyruvate; Pyruvates; Recommendation; Relative (related person); Reporting; Research; Scanning; Serum; Site; Skeletal Muscle; Skin Cancer; Sodium-Hydrogen Antiporter; Staging; Suggestion; Testing; Testis; Therapeutic; Tissues; Toxic effect; Translations; United States; Virulent; Xenograft procedure; base; cancer cell; cariporide; chemotherapy; design; human subject; inhibitor/antagonist; male; melanoma; metaiodobenzylguanidine; method development; mortality; neoplastic cell; nucleoside triphosphate; pH Homeostasis; prevent; respiratory; response; temozolomide; tumor; tumor xenograft; vacuolar H+-ATPase

Melanoma is the most virulent of all the skin cancers. While often cured by early surgical excision, there is no generally effective method for treating disseminated disease. We propose to sensitize melanoma to cisplatin and cyclophosphamide utilizing a method for selective acidification of melanomas that we have recently developed. The basic strategy is to induce systemic hyperglycemia by i.v. infusion of glucose to maintain a vascular glucose concentration of 261 mM (465 mg/dL) to drive lactate production. To maximize tumor lactate production meta-iodobenzylguanidine (MIBG), an inhibitor of site-1 of the respiratory electron transport chain, is administered. Lactate is then trapped inside the tumor cells by administration of an inhibitor of the monocarboxylic acid transporter (MCT). In previous studies we have used α−CN-4-hydroxycinnamic acid (CNCn). By this method we have been able to maintain the intracellular pH (pHi) of DB1 melanoma xenografts at 6.2-6.4 for ~40 min.; the pHi of brain, liver and skeletal muscle were unaffected. Tumor levels of nucleoside triphosphates (NTP) decreased markedly, whereas the bioenergetics of muscle and brain were unaffected; the liver showed ~30% decrease in ATP. Since normal tissues do not exhibit a Warburg Effect, a therapeutic gain should result from this method. It is well known that the alkylating agents cisplatin and cyclophosphamide are activated in acidic media, thus, we anticipate that these drugs will be selectively activated in the tumor by selective metabolic tumor acidification. In Aim 1 we propose to adapt the selective metabolic acidification procedure to clinical translation by eliminating CNCn, which is not FDA approved, or replacing CNCn and with lonidamine, an agent that inhibits the MCT and also blocks oxidative phosphorylation by preventing pyruvate transfer into mitochondria. Lonidamine is widely used in the clinic in Europe, and the FDA has granted INDs for its use in the USA. Once the optimum selective acidification procedure is perfected on the DB1 tumor, we will determine if this method enhances the efficacy of cisplatin and cyclophosphamide against xenografts of this tumor in nude mice. Aim 2 will utilize histopathology, serum enzyme assays and a variety of functional tests utilizing our expertise in MRS and MRI as well as NIR optical redox scanning to examine the toxicity of these procedures to various critical normal tissues.

黑色素瘤是所有皮肤癌中最致命的。虽然通常通过早期手术切除来治愈，但没有 一般有效的治疗播散性疾病的方法。我们建议使黑色素瘤对顺铂和 环磷酰胺利用我们最近开发的一种方法选择性酸化黑色素瘤。 基本策略是静脉注射诱导全身性高血糖。输注葡萄糖以维持血管 葡萄糖浓度为261 mM(465 mg/dL)，以推动乳酸生产。为了最大限度地增加肿瘤乳酸 生产呼吸电子传递链1位的抑制剂--间碘苯甲基胍(MIBG)， 是被执行的。然后乳酸被困在肿瘤细胞内，通过给药一种抑制 单羧酸转运蛋白(MCT)。在以前的研究中，我们使用了α−CN-4-羟基肉桂酸 (CNCn)。通过这种方法，我们已经能够维持DB1黑色素瘤移植瘤的细胞内pH(Phi) 在6.2-6.4℃作用40分钟，对脑、肝和骨骼肌的pH值无影响。肿瘤核苷水平 三磷酸盐(NTP)显著降低，而肌肉和脑的生物能量学没有受到影响； 肝脏中的三磷酸腺苷含量下降约30%。由于正常组织不会表现出华宝效应，治疗上的收获 应该是这种方法的结果。众所周知，烷化剂顺铂和环磷酰胺是 在酸性介质中被激活，因此，我们预计这些药物在肿瘤中将被选择性地激活 选择性代谢性肿瘤酸化。在目标1中，我们建议采用选择性代谢性酸化 通过取消未经FDA批准的CNCn或将CNCn替换为 氯硝胺，一种抑制MCT并通过阻止丙酮酸而阻止氧化磷酸化的试剂 转移到线粒体中。氯硝胺在欧洲的临床上被广泛使用，FDA已经批准了INDS 因为它在美国的使用。一旦DB1肿瘤的最佳选择性酸化程序得到完善，我们 将确定这种方法是否增强了顺铂和环磷酰胺对这种异种移植瘤的疗效 裸鼠体内的肿瘤。AIM 2将利用组织病理学、血清酶分析和各种功能测试 利用我们在MRS和MRI以及近红外光学氧化还原扫描方面的专业知识来检测这些物质的毒性 对各种关键的正常组织进行手术。