Safety/Efficacy of Liposomal Reversan, a novel MRP1 modulator for Cancer Therapy

脂质体 Reversan（一种用于癌症治疗的新型 MRP1 调节剂）的安全性/功效

• 批准号: 7612373
• 负责人: ARINDAM SEN
• 金额: $ 10.46万
• 依托单位: BUFFALO BIOLABS, LLC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7612373
• 关键词: ABCC1 gene; Adverse drug effect; Antineoplastic Agents; Chemicals; Clinical; Clinical Trials; Cytochromes; Data; Development; Dimethyl Sulfoxide; Drug Combinations; Drug Efflux; Drug Evaluation; Drug Formulations; Drug Kinetics; Drug resistance; Etoposide; Failure; Generations; Goals; Hand; In Vitro; Ion Channel; Knowledge; Liposomes; Malignant Neoplasms; Metabolic Clearance Rate; Modeling; Multi-Drug Resistance; Multidrug Resistance Associated Protein 1; Multidrug Resistance-Associated Proteins; Names; Neuroblastoma; Normal tissue morphology; Oral; Organ; Outcome; P-Glycoprotein; P-Glycoproteins; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plague; Play; Principal Investigator; Process; Program Development; Proteins; Pump; Refractory; Research Design; Resistance; Role; Roswell Park Cancer Institute; Safety; Schedule; Screening procedure; Small Business Technology Transfer Research; Testing; Therapeutic Index; Time; Tissues; Toxic effect; Toxicology; Treatment Failure; Treatment Protocols; Vesicle; Vincristine; Work; base; cancer cell; cancer therapy; chemotherapy; efflux pump; experience; fight against; improved; in vivo; in vivo Model; inhibitor/antagonist; killings; model development; multi drug transporter; neoplastic cell; novel; programs; public health relevance; resistance mechanism; success; treatment strategy; tumor; uptake

DESCRIPTION (provided by applicant): One of the major problems in the fight against cancer is the intrinsic or acquired resistance of tumors to current cancer treatments, particularly that associated with multidrug transporters (MDT; e.g. P-glycoprotein (P-gp) and the multidrug associated protein (MRP1)). The clinical failures of early P-gp inhibitors, which either caused non-specific toxicity or pharmacokinetic interactions with conventional chemotherapy agents, has significantly diminished the enthusiasm of pharmaceutical companies to develop MDT inhibitors. Nevertheless, drug resistance associated with these transporters is still a serious problem and the development of inhibitors against these proteins must be revisited using the knowledge and experience gained from previous failures to significantly increase the chances for success. The studies outlined in this proposal center around the optimization of Reversan, a MRP1 inhibitor that surpasses the activity of many known inhibitors of this MDT in the absence of toxicity. Our goal is to develop Reversan as an anti-cancer agent to be used together with standard chemotherapy to improve the efficacy of these conventional agents using liposomal formulations of Reversan or Reversan-drug combinations. Liposomal vehicles for in vivo delivery offer important features for tumor delivery of molecules, including decreased systemic clearance rates, decreased systemic toxicity as a result of decreased uptake of formulated agents by normal tissues and at the same time improved efficacy due to increased uptake of the formulated agents by tumors. The data generated under this proposal will form the basis for the rational design of studies involving other conventional agents as well as for clinical trials using Reversan combinations to assess the potential of Reversan as an anti-cancer agent. The significance of this project lies in its potential for identifying new treatment strategies for drug refractory cancers, such as neuroblastoma, that are currently faced with limited treatment options due to inherent and acquired drug resistance caused by MRP1 or MDTs in general. PUBLIC HEALTH RELEVANCE: One of the major problems in the fight against cancer is resistance to current cancer treatments, particularly resistance caused by multidrug transporters that pump standard cancer drugs out of cancer cells. Inhibitors of these transporters, such as Reversan-the focus of this proposal, when used together with standard chemotherapy should greatly increase the killing of tumor cells by allowing the drugs to stay in tumor cells. Thus, Reversan has the potential to improve the clinical outcome for patients with limited treatment options due to multidrug resistance.

描述(申请人提供)：抗癌斗争中的主要问题之一是肿瘤对当前癌症治疗方法的固有或获得性耐药性，特别是与多药转运体(MDT；例如P-糖蛋白(P-gp)和多药相关蛋白(MRP1))相关的耐药性。早期P-gp抑制剂的临床失败，导致与传统化疗药物的非特异性毒性或药代动力学相互作用，极大地降低了制药公司开发MDT抑制剂的积极性。然而，与这些转运蛋白相关的耐药性仍然是一个严重的问题，必须利用从以前的失败中获得的知识和经验来重新审视针对这些蛋白质的抑制剂的开发，以显著增加成功的机会。这项提案中概述的研究围绕Reversan的优化展开，Reversan是一种MRP1抑制剂，在没有毒性的情况下超过了这种MDT的许多已知抑制剂的活性。我们的目标是开发Reversan作为一种抗癌药物，与标准化疗一起使用，以提高这些使用Reversan脂质体或Reversan与药物组合的传统药物的疗效。脂质体体内给药载体为肿瘤分子的传递提供了重要的特征，包括降低了系统清除率，减少了由于正常组织对制剂的摄取而导致的全身毒性，同时由于肿瘤对制剂的摄取增加而提高了疗效。根据这一建议产生的数据将成为涉及其他传统药物的研究的合理设计的基础，以及使用Reversan组合评估Reversan作为抗癌药物的潜力的临床试验的基础。该项目的意义在于它有可能确定新的药物难治性癌症的治疗策略，如神经母细胞瘤，由于MRP1或MDT引起的固有和获得性耐药性，这些癌症目前面临的治疗选择有限。与公共卫生相关：抗击癌症的主要问题之一是对当前癌症治疗的抗药性，特别是从癌细胞中输送标准抗癌药物的多药转运体造成的抗药性。这些转运蛋白的抑制剂，如Reversan-这一提案的重点，当与标准化疗一起使用时，应该会通过允许药物留在肿瘤细胞中而大大增加对肿瘤细胞的杀伤力。因此，Reversan有可能改善因多药耐药而治疗选择有限的患者的临床结果。