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有毒的。虽然经常被早期手术惊喜治愈，但没有 通常有效治疗传播疾病的方法。我们建议将黑色素瘤感知到顺铂和 环磷酰胺利用一种我们最近开发的黑色素瘤的选择性酸化。 基本策略是通过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1mm（465 mg/dl），以驱动乳酸产生。最大化肿瘤乳酸 生产元二苯甲酰氨酸（MIBG），呼吸电子传输链1的抑制剂， 被管理。然后通过给予乳酸在肿瘤细胞中捕获 单羧酸转运蛋白（MCT）。在先前的研究中，我们使用了α-CN-4-羟基霉素酸 （CNCN）。通过这种方法，我们能够维持DB1黑色素瘤Xenographys的细胞内pH（PHI） 在6.2-6.4持续约40分钟。大脑，肝脏和骨骼肌的PHI不受影响。肿瘤水平 三磷酸盐（NTP）显着改善，而肌肉和大脑的生物能学不受影响。这 肝脏显示ATP降低约30％。由于正常组织不存在Warburg效应，因此可以获得治疗性增长 应该由这种方法产生。众所周知，烷基化剂顺铂和环磷酰胺是 因此，在酸性培养基中激活，我们预计这些药物将通过 选择性代谢肿瘤酸化。在AIM 1中，我们建议适应选择性代谢酸化 通过消除未经FDA批准的CNCN或替换CNCN并使用CNCN进行的临床翻译的程序 Lonidamine，一种抑制MCT并通过预防丙酮酸来阻断氧化磷酸化的药物 转移到线粒体中。 Lonidamine在欧洲的诊所广泛使用，FDA已授予INDS 在美国使用。一旦最佳选择性酸化程序在DB1肿瘤上是完美的 将确定这种方法是否提高了顺铂和环磷酰胺对此的异种移植的效率 裸鼠的肿瘤。 AIM 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光学氧化还原扫描中的专业知识来检查这些毒性 各种关键正常组织的程序。