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: 7740882
• 负责人: JERRY D GLICKSON
• 金额: $ 47.05万
• 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/7740882
• 关键词: Adrenal Glands; Affect; Bioenergetics; Biological Assay; Blood Vessels; Bone Marrow; Brain; Cisplatin; Clinic; Clinical; Cyclophosphamide; Disease; Dose; Dose-Limiting; Electron Transport; Energy-Generating Resources; Enzymes; Europe; Excision; Exhibits; FDA approved; Glucose; Grant; Heart; Histopathology; Hyperglycemia; Infusion procedures; Kidney; Lactic acid; Life; Liver; Lonidamine; Magnetic Resonance Imaging; Maximum Tolerated Dose; Measurement; Mechlorethamine; Melphalan; Metabolic; Metabolism; Methods; Mitochondria; Mus; Muscle; Myalgia; Normal Cell; Normal tissue morphology; Nude Mice; Operative Surgical Procedures; Optics; Oxidation-Reduction; Oxidative Phosphorylation; Pain; Procedures; Production; Protocols documentation; Pyruvate; Pyruvates; Relative (related person); Scanning; Serum; Site; Skeletal Muscle; Skin Cancer; Testing; Testis; Therapeutic; Tissues; Toxic effect; Translations; Virulent; Xenograft procedure; base; cancer cell; chemotherapy; human subject; inhibitor/antagonist; male; melanoma; metaiodobenzylguanidine; neoplastic cell; prevent; respiratory; response; tumor; tumor xenograft

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，但没有 治疗播散性疾病的普遍有效方法。我们建议使黑色素瘤对顺铂敏感，并 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注射诱导全身高血糖。输注葡萄糖以维持血管 葡萄糖浓度为 261 mM (465 mg/dL) 以驱动乳酸产生。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， 被管理。然后，通过给予乳酸抑制剂，乳酸被捕获在肿瘤细胞内。 单羧酸转运蛋白（MCT）。在之前的研究中我们使用了α−CN-4-羟基肉桂酸 （数控）。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；大脑、肝脏和骨骼肌的 pHi 不受影响。肿瘤核苷水平 三磷酸盐（NTP）显着下降，但肌肉和大脑的生物能不受影响；这 肝脏显示 ATP 减少约 30%。由于正常组织不表现出瓦伯格效应，因此治疗增益 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： 选择性代谢肿瘤酸化。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。氯尼达明在欧洲临床广泛使用，FDA已授予IND 以便在美国使用。一旦 DB1 肿瘤的最佳选择性酸化程序完善，我们 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 裸鼠体内的肿瘤。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。