The Use of Hyperthermia and Copper Chelation to Overcome Cisplatin Resistance

使用热疗和铜螯合克服顺铂耐药性

• 批准号: 8452604
• 负责人: Chelsea Dawn Landon
• 金额: $ 0.22万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8452604
• 关键词: Accounting; Address; Adjuvant; Adjuvant Chemotherapy; Biodistribution; Biological Preservation; Bladder; Blood Vessels; Cancer Patient; Carrier Proteins; Cell Death; Cell membrane; Cell surface; Cells; Chelating Agents; Cisplatin; Clinic; Clinical; Collaborations; Copper; Copper Chelation; DNA Adduction; Data; Disease; Dose-Limiting; Doxorubicin; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug Targeting; Drug Transport; Drug resistance; Encapsulated; Environment; Exhibits; FDA approved; Goals; Heating; Hyperthermia; In Vitro; Induced Hyperthermia; Knowledge; Lead; Liposomes; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Membrane; Methods; Modality; Molecular; Muscle; Neoplasm Metastasis; Newly Diagnosed; Normal tissue morphology; Patients; Penetration; Perfusion; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Platinum; Play; Quality of life; Radical Cystectomy; Regimen; Resistance; Role; Site; Survival Rate; System; Therapeutic; Tissues; Toxic effect; Transition Temperature; Treatment Efficacy; Tumor Tissue; Work; base; cancer cell; cancer therapy; cancer type; cell killing; chelation; clinical application; cytotoxicity; drug efficacy; effective therapy; extracellular; hypocupremia; improved; in vivo; in vivo Model; neoplastic cell; novel; novel therapeutics; resistance mechanism; response; standard of care; synergism; treatment strategy; tumor; uptake

DESCRIPTION (provided by applicant): Drug resistance, along with normal tissue toxicity, remains a major obstacle for the successful treatment of cancer. Targeting these resistance mechanisms will result in increased tumor cell death, decreased tumor size, and may lead to overall patient survival. The purpose of this study is to understand how hyperthermia (HT) alters cellular resistance mechanisms and to exploit these abilities to increase drug delivery to the tumor site. The work outlined in this application will focus on targeting inefficiencies in drug transport and inherent cellular resistance mechanisms. Specifically, we propose to combine the many therapeutic benefits of HT with copper chelators and cisplatin-encapsulated thermosensitive liposomes (TSL) to target and treat muscle invasive disease in bladder cancer patients. Our group has recently developed a TSL that encapsulates cisplatin. Using this drug formulation in combination with HT is a modality that will overcome inefficiencies in drug transport, and reduce the undesirable toxicity to other tissues. HT is known to interact synergistically with multiple chemotherapeutic drugs, including cisplatin, but the molecular mechanisms underlying this interaction remain unclear. Copper transporter protein 1 (Ctr1) is a major regulator of cellular cisplatin uptake. Our preliminary data show that HT increases cisplatin uptake and platinum-DNA adduct formation in wild type but not in Ctr1-/- cells indicating the involvement of Ctr1 in this synergism. One goal of our study is to use copper chelators to create an environment of copper deficiency in order to increase Ctr1 expression levels on the cell surface. Increased Ctr1 membrane expression in the presence of cisplatin will lead to increased drug uptake, accumulation, and cytotoxicity. Enhancing cisplatin uptake and efficacy by increasing Ctr1 expression via copper chelation has yet to be studied and could prove to be an effective treatment modality with clinical applicability and potential. We hypothesize that utilizing the combination of a TSL-based system paired with Ctr1 manipulation will increase cisplatin delivery and uptake in tumor cells and will prove to be an effective anti-cancer strategy. We will address our hypothesis with two Specific Aims. In vitro, we plan to elucidate the role Ctr1 plays in the synergistic interaction between cisplatin and HT and use this knowledge to increase drug efficacy. In vivo, we will examine the pharmacokinetics and anti-tumor effect of the cisplatin-TSL and HT combination and apply the information derived from the Ctr1 studies to improve this combinational treatment to increase the overall anti- cancer effect. Since cisplatin and copper chelators are currently both FDA approved drugs, our proposed treatment regime should have a relatively straightforward transition into the clinic.

描述（由申请人提供）：耐药性，沿着正常组织毒性，仍然是成功治疗癌症的主要障碍。靶向这些耐药机制将导致肿瘤细胞死亡增加，肿瘤大小减小，并可能导致患者总体生存。本研究的目的是了解高温（HT）如何改变细胞的抵抗机制，并利用这些能力来增加药物输送到肿瘤部位。本申请中概述的工作将集中在靶向药物转运和固有细胞耐药机制中的效率低下。具体而言，我们建议将HT的许多治疗益处与铜螯合剂和顺铂包封的热敏脂质体（TSL）结合联合收割机，以靶向和治疗膀胱癌患者的肌肉浸润性疾病。 我们小组最近开发了一种包裹顺铂的TSL。使用这种药物制剂与HT组合是一种将克服药物转运效率低下并降低对其他组织的不良毒性的方式。已知HT与多种化疗药物（包括顺铂）协同相互作用，但这种相互作用的分子机制仍不清楚。铜转运蛋白1（Ctr 1）是细胞顺铂摄取的主要调节因子。我们的初步数据表明，HT增加顺铂的摄取和铂-DNA加合物的形成，在野生型，但不是在Ctr 1-/-细胞表明Ctr 1参与这种协同作用。我们研究的一个目标是使用铜螯合剂来创造一个铜缺乏的环境，以增加细胞表面Ctr 1的表达水平。在顺铂存在下Ctr 1膜表达增加将导致药物摄取、蓄积和细胞毒性增加。通过铜螯合增加Ctr 1表达来增强顺铂摄取和疗效还有待研究，可能被证明是一种具有临床适用性和潜力的有效治疗方式。 我们假设，利用基于TSL的系统与Ctr 1操作的组合将增加顺铂在肿瘤细胞中的递送和摄取，并将被证明是一种有效的抗癌策略。我们将通过两个具体目标来解决我们的假设。在体外，我们计划阐明Ctr 1在顺铂和HT之间的协同相互作用中发挥的作用，并利用这些知识来提高药物疗效。在体内，我们将检查顺铂-TSL和HT组合的药代动力学和抗肿瘤作用，并应用来自Ctr 1研究的信息来改进该组合治疗以增加总体抗癌作用。由于顺铂和铜螯合剂目前都是FDA批准的药物，我们提出的治疗方案应该有一个相对简单的过渡到临床。