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最致命的。虽然经常通过早期手术切除治愈，但没有 通常有效的治疗播散性疾病的方法。我们建议将黑色素瘤对顺铂敏感， 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内输注葡萄糖诱导全身性高血糖症，以维持血管紧张素转换酶活性。 葡萄糖浓度为26 mM（465 mg/dL）以驱动乳酸盐产生。最大化肿瘤乳酸 生产间碘苄胍（MIBG），一种呼吸电子传递链位点1的抑制剂， 被管理。然后，通过施用抗肿瘤药物的抑制剂，将乳酸盐捕获在肿瘤细胞内。 单羧酸转运蛋白（MCT）。在以前的研究中，我们使用α−CN-4-羟基肉桂酸 （CNCn）.通过这种方法，我们能够维持DB 1黑色素瘤异种移植物的细胞内pH值（pHi） 在6.2-6.4下约40 min;脑、肝和骨骼肌的pHi不受影响。肿瘤核苷水平 三磷酸盐（NTP）显著降低，而肌肉和大脑的生物能量学不受影响; 肝脏显示ATP减少约30%。由于正常组织不表现出瓦尔堡效应，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 因此，我们预期这些药物将在肿瘤中被选择性激活， 选择性代谢肿瘤酸化。在目标1中，我们建议调整选择性代谢酸化 通过删除未经FDA批准的CNCn，或用CNCn替代CNCn， 氯尼达明，一种抑制MCT并通过阻止丙酮酸来阻断氧化磷酸化的药物 转移到线粒体中。氯尼达明在欧洲临床上应用广泛，FDA已批准IND 在美国使用。一旦在DB 1肿瘤上完善了最佳选择性酸化程序， 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物的功效 裸鼠肿瘤。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， 各种重要的正常组织。