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

基本信息

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
项目类别：
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

项目摘要

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毒性最强的，虽然通常可以通过早期手术切除来治愈，但目前还没有治愈方法。我们建议使黑色素瘤对顺铂敏感，这是治疗播散性疾病的普遍有效方法。环磷酰胺利用我们最近开发的选择性酸化黑色素瘤的方法。基本策略是通过静脉输注葡萄糖诱导全身高血糖以维持血管。 261 mM (465 mg/dL) 的葡萄糖可驱动乳酸浓度最大化，以最大化肿瘤乳酸。生产间碘苄基胍 (MIBG)，呼吸电子传递链位点 1 的抑制剂，然后通过施用抑制剂将乳酸捕获在肿瘤细胞内。在之前的研究中，我们使用了α−CN-4-羟基肉桂酸。 (CNCn) 通过这种方法，我们能够维持 DB1 黑色素瘤异种移植物的细胞内 pH (pHi)。 6.2-6.4 约 40 分钟；脑、肝脏和骨骼肌的 pHi 不受影响。三磷酸盐（NTP）显着下降，而肌肉和大脑的生物能未受影响；肝脏显示 ATP 减少约 30%，因为正常组织不表现出瓦伯格效应，因此具有治疗效果。众所周知，烷化剂顺铂和环磷酰胺是由该方法产生的。在酸性介质中激活，因此，我们预计这些药物将通过以下方式在肿瘤中选择性激活：在目标 1 中，我们建议采用选择性代谢酸化。通过消除未经 FDA 批准的 CNCn 或替换 CNCn 并使用氯尼达明，一种抑制 MCT 的药物，还可以通过阻止丙酮酸来阻断氧化磷酸化转移到线粒体中的氯尼达明在欧洲临床广泛使用，FDA已授予IND。一旦最佳选择性酸化程序在 DB1 肿瘤上得到完善，我们就将其用于美国。将确定该方法是否增强顺铂和环磷酰胺针对该异种移植物的功效目标 2 将利用组织病理学、血清酶测定和各种功能测试。利用我们在 MRS 和 MRI 以及 NIR 光学氧化还原扫描方面的专业知识来检查这些物质的毒性对各种重要正常组织进行手术。