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.

异环磷酰胺 (IFO) 是一种烷基化氧氮磷碱，已被发现对于治疗复发性实体瘤以及对其他化疗药物治疗后反应不佳的患者非常有效。然而，IFO 的疗效因肾毒性发生率高而受到严重限制。该提案需要对 IFO 诱导的肾损伤中涉及的迄今未知的机制进行全面研究，并通过给予甘氨酸 (Gly) 来预防此类损伤，我们发现甘氨酸在体外和体内都是有效的细胞保护剂。我们的最终目标是开发一种临床适用的方案，涉及使用 IFO 给予甘氨酸，以防止接受这种抗肿瘤药物治疗的癌症患者出现肾毒性。要探讨的主要假设是，IFO 治疗期间诱导肾损伤是通过 IFO 的一种或多种活性代谢物（即 4-羟基-IFO (4-OH-IFO) 和 4-OH-IFO）在肾皮质中的积累介导的。 /或异磷酰胺芥子气(IPM)，继发于氯乙醛(CAA)和/或丙烯醛(ACR)消耗[GSH]。这些代谢物可能与质膜或线粒体膜蛋白的 SH 基团发生反应，从而损害细胞完整性。另一种但并非相互排斥的假设是，IFO 治疗期间引起肾损伤的主要机制是通过 CAA 和/或 ACR 抑制线粒体氧化代谢介导的，导致能量产生缺陷、多种代谢异常，从而导致细胞损伤。然而，同时口服补充 Gly 和 IFO 将通过维持肾近端小管的完整性来减轻 IFO 诱导的肾毒性，而不会减弱 IFO 的抗肿瘤作用。当前提案的独特之处在于：（a）成功开发了用于研究 IFO 诱导的肾毒性的大鼠模型系统； (b) 使用核磁共振（NMR）、气相色谱-质谱（GC-MS）、LC-MS-MS、激光扫描共焦显微镜和分子生物学技术来探索导致 IFO 的生化/分子病变-诱发肾损伤； (c) 通过口服补充甘氨酸来预防此类损伤。拟议的研究具有临床和科学意义。所生成的数据对于预防与癌症化疗相关的肾功能障碍可能具有相当重要的意义，从而可以提高癌症患者的治疗效果并提高生存率。