(9) Therapeutic strategies to mitigate toxicities of platinum-based therapeutics

(9) 减轻铂类药物毒性的治疗策略

• 批准号: 9303693
• 负责人: Navjot Pabla
• 金额: $ 50.33万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-03 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303693
• 关键词: Acetylcysteine; Acute; Adult; Adverse effects; Affect; Antineoplastic Agents; Binding; Biochemical; Biological Assay; Cancer cell line; Cell Line; Cells; Child; Chronic; Cisplatin; Clinical; Cochlea; Data; Dose-Limiting; Drug Interactions; Evaluation; Event; Foundations; Future; Genetic; Goals; Human; Hybrids; In Situ; In Vitro; Incidence; Kidney; Lead; Libraries; Life; Malignant - descriptor; Mammalian Cell; Measures; Mediating; Mus; Non-Small-Cell Lung Carcinoma; Organic Anion Transporters; Organic Cation Transporter; Pathway interactions; Patients; Peripheral Nerves; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Physiological; Platinum; Prevention; Process; Property; Proteins; Proteomics; Publishing; RNA Interference; Role; Severities; Solid Neoplasm; Source; Specificity; System; Testing; Therapeutic; Tissues; Toxic effect; Treatment Protocols; Tubular formation; Tyrosine Kinase Inhibitor; Tyrosine Phosphorylation; Work; Xenobiotics; Xenograft procedure; Zebrafish; base; chemotherapy; clinical practice; hearing impairment; in vivo; in vivo Model; inhibitor/antagonist; interest; mouse model; nephrotoxicity; neurotoxicity; ototoxicity; prophylactic; response; screening; small molecule; targeted agent; treatment strategy; tumor; tumor xenograft; uptake

ABSTRACT Cisplatin is one of the most widely used anticancer agents, including for the treatment of solid tumors in children and adults. The clinical use of cisplatin is associated with dose-limiting damage to renal tubular cells (nephrotoxicity), which occurs in up to 40% of patients despite intensive prophylactic measures, as well as with toxicity to cochlea (ototoxicity) and peripheral nerves (neurotoxicity), and these complications may limit further treatment or even threaten life. There is currently no known specific treatment for cisplatin-induced toxicities, and mechanistic details of these side effects remain poorly understood. We have recently found that the ability of platinum chemotherapeutics to cause damage to healthy tissues cells is dependent on organic cation transporters (OCT) and, for renal tubular cells, organic anion transporters (OAT) as well. In mice, these processes were found to be regulated by the two pairs of closely related transporters, Oct1/Oct2 that regulate cellular uptake of cisplatin, and Oat1/Oat3 that regulate renal uptake of a cisplatin mercapturic acid metabolite that acts as a precursor of a potent nephrotoxin. We found that the function of these 4 transporters can be potently inhibited by the tyrosine kinase inhibitor nilotinib, through non-competitive mechanisms. In the current proposal, we outline three sets of related studies that will further test and refine the validity of our central hypothesis that targeted inhibition of OCT and OAT function with nilotinib will specifically affect accumulation of cisplatin in healthy target tissues and affect its downstream toxic effects: (i) Using various in vitro and in vivo models, including zebrafish and mice, we will further determine the qualitative and quantitative effects of nilotinib on the function of Oct1/Oct2 and Oat1/Oat3; (ii) Studies in zebrafish and mice with or without specific transporters and kinases of interest will determine the direct contribution of these proteins to cisplatin-related toxicity, including nephrotoxicity, ototoxicity, and neurotoxicity, as well as drug disposition properties and drug- drug interaction potentials; (iii) Using mice with or without human tumor xenografts derived from replicating cell lines or patient tumors, we will determine the direct contribution of these proteins to cisplatin-related anticancer efficacy, and the in vivo effects of nilotinib on this phenotype. The demonstration of reduced cisplatin-induced toxicity through inhibition of critical transporters regulating access of the drug to healthy tissues will provide the foundation for additional studies in the future aimed at ameliorating this agent's debilitating side effects in routine clinical practice.

抽象的 顺铂是最广泛使用的抗癌药物之一，包括用于治疗实体瘤 儿童和成人。顺铂的临床使用与肾小管细胞的剂量限制性损伤有关 （肾毒性），尽管采取了强化预防措施，仍有高达 40% 的患者发生这种情况，以及 对耳蜗（耳毒性）和周围神经（神经毒性）的毒性，这些并发症可能会进一步限制 治疗甚至威胁生命。目前尚无已知的针对顺铂引起的毒性的具体治疗方法， 这些副作用的机制细节仍然知之甚少。我们最近发现，这种能力 铂化疗药物对健康组织细胞造成损害的程度取决于有机阳离子 转运蛋白（OCT），对于肾小管细胞，还有有机阴离子转运蛋白（OAT）。在小鼠中，这些 研究发现，这一过程受到两对密切相关的转运蛋白 Oct1/Oct2 的调节，它们调节 顺铂的细胞摄取，以及调节顺铂硫醇酸代谢物的肾脏摄取的 Oat1/Oat3 它是强效肾毒素的前体。我们发现这4个转运蛋白的功能可以是 酪氨酸激酶抑制剂尼罗替尼通过非竞争性机制有效抑制。在当前 提案中，我们概述了三组相关研究，这些研究将进一步测试和完善我们中心研究的有效性 假设用尼洛替尼靶向抑制 OCT 和 OAT 功能将特别影响 顺铂在健康靶组织中的作用并影响其下游毒性作用：（i）使用各种体外和体内 模型，包括斑马鱼和小鼠，我们将进一步确定定性和定量的影响 尼洛替尼对 Oct1/Oct2 和 Oat1/Oat3 功能的影响； (ii) 对斑马鱼和小鼠进行的研究，有或没有特定的 感兴趣的转运蛋白和激酶将决定这些蛋白质对顺铂相关的直接贡献 毒性，包括肾毒性、耳毒性和神经毒性，以及药物处置特性和药物- 药物相互作用潜力； (iii) 使用具有或不具有源自复制细胞的人类肿瘤异种移植物的小鼠 细胞系或患者肿瘤，我们将确定这些蛋白质对顺铂相关抗癌的直接贡献 疗效以及尼罗替尼对该表型的体内影响。顺铂诱导的减少的证明 通过抑制调节药物进入健康组织的关键转运蛋白的毒性将提供 为未来进一步研究奠定基础，旨在改善该药物的衰弱副作用 常规临床实践。