PREVENTION OF IFOSFAMIDE INDUCED NEPHROTOXICITY

预防异环磷酰胺引起的肾毒性

• 批准号: 6784225
• 负责人: ITZHAK NISSIM
• 金额: $ 26.78万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6784225
• 关键词: MESNA; acute renal failure; adenosine triphosphate; aerobiosis; brush border membrane; chemoprevention; cyclophosphamide; drug interactions; glutathione; glycine; ifosfamide; kidney pharmacology; laboratory rat; mitochondria; oral administration; renal cortex; renal toxin

Ifosfamide (IFO), an alkylating oxazaphosphorine, has been found to be very effective for the treatment of relapsed solid tumors and in patients who respond poorly following treatment with other chemotherapeutic agents. However, the efficacy of IFO is severely limited by a high incidence of nephrotoxicity. This proposal entails a comprehensive investigation of the as yet unknown mechanism(s) involved in IFO- induced renal injury and prevention of such injury by administration of glycine (Gly), which we found to be an effective cytoprotective agent both in vitro and in vivo. Our ultimate goal is to develop a clinically applicable protocol involving administration of glycine with IFO to prevent nephrotoxcity in cancer patients treated with this antineoplastic drug. The main hypothesis to be explored is that the induction of renal injury during IFO treatment is mediated via accumulation in the kidney cortex of one or more of the active metabolites of IFO, i.e., 4-hydroxy-IFO (4- OH-IFO) and/or isophosphoramide mustard (IPM), secondary to depletion of [GSH] by chloroacetaldehyde (CAA) and/or acrolein (ACR). These metabolites may react with SH-groups of the plasma membrane or mitochondrial membrane proteins, thereby damaging cellular integrity. An alternative, but not mutually exclusive hypothesis is that the primary mechanism in evoking renal injury during IFO treatment is mediated via inhibition of mitochondrial oxidative metabolism by CAA and/or ACR, resulting in defective energy production, multiple metabolic abnormalities, and thereby, cellular damage. However, concomitant oral supplementation of Gly with IFO will attenuate IFO-induced nephrotoxicity by maintaining the renal proximal tubule integrity without diminishing the antitumor action of IFO. Unique features of the current proposal are: (a) the successful development of a rat model system for investigation of IFO-induced renal toxicity; (b) the use of Nuclear Magnetic Resonance (NMR), Gas Chromatography-Mass Spectrometry (GC-MS), LC-MS-MS, Laser- Scanning Confocal Microscopy and techniques of molecular biology to explore the biochemical/molecular lesions responsible for IFO-induced renal injury; and (c) a prevention of such injury by oral supplementation of Gly. The proposed studies are of clinical as well as scientific significance. The data to be generated will potentially have considerable importance for prevention of renal dysfunction associated with cancer chemotherapy, and thus allow for a greater therapeutic efficacy and enhanced survival of cancer patients.

发现烷基化的阿沙唑啉（Ifosfamide）（IFO）对治疗复发的实体瘤以及与其他化学治疗剂治疗后反应不佳的患者非常有效。但是，IFO的疗效受到肾毒性高发生率的严重限制。该提案需要对涉及肾脏损伤的尚未知道的机制进行全面研究，并通过给药甘氨酸（GLY）预防这种损伤，我们发现这是体外和体内有效的细胞保护剂。我们的最终目标是制定一项临床适用的方案，涉及用IFO施用甘氨酸，以防止用这种抗肿瘤药物治疗的癌症患者的肾毒性。要探讨的主要假设是，IFO治疗期间肾脏损伤的诱导是通过在肾皮质中积累的一个或多个IFO活性代谢物的积累，即4-羟基-IFO（4- oh-ifo）（4- oh-ifo）和/或/或/磷酸酰胺（IPM），二级和ca/ca/ca ca/ca cai/cae cai/cae cai/ca/ca/ca。丙烯醛（ACR）。这些代谢产物可能与质膜或线粒体膜蛋白的SH组反应，从而损害细胞完整性。一种替代性但不是互斥的假设是，通过CAA和/或ACR抑制线粒体氧化代谢，唤起IFO治疗期间肾损伤的主要机制是导致能量产生，多种代谢异常的缺陷，从而导致细胞损伤。但是，通过维持肾脏近端小管完整性而不会减少IFO的抗肿瘤作用，可以通过维持肾近端小管的完整性来减轻IFO诱导的肾毒性，从而减弱IFO诱导的肾毒性。当前建议的独特特征是：（a）成功开发大鼠模型系统，以研究IFO诱导的肾脏毒性； （b）使用核磁共振（NMR），气相色谱 - 质量光谱法（GC-MS），LC-MS-MS，激光扫描共聚焦显微镜以及分子生物学的技术探索生物化学/分子病变，导致IFO诱导的肾脏诱导的肾脏损伤； （c）通过补充gly来预防这种伤害。拟议的研究具有临床和科学意义。要生成的数据对于预防与癌症化学疗法相关的肾功能障碍具有很大的重要性，从而允许更大的治疗功效和癌症患者的生存率增强。