BIOTRANSFORMATION STUDIES WITH OXYALIPLATIN

奥沙利铂的生物转化研究

基本信息

批准号：
2443004
负责人：
STEPHEN G CHANEY
金额：
$ 14.97万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-07-01 至 1999-06-30
项目状态：
已结题

项目摘要

DESCRIPTION: (Applicant's Abstract) Oxaliplatin (1-trans)1,2- diaminocyclohexaneoxalatoplatinum (II)is a second generation platinum compound that has shown significant promise in European clinical trials because of efficacy against cisplatin-resistant tumors. (1) The applicant has developed HPLC techniques for resolving and quantitating the major diaminocyclohexane (dach)-Pt biotransformations of oxaliplatin. He plans to study the stability and mechanism(s) of displacement of the oxalato leaving ligand in plasma and the intracellular biotransformations of oxaliplatin. These studies will characterize the mechanisms and kinetics for activation of oxaliplatin and provide valuable information for the identification of biotransformation products and pathways in a companion clinical study of oxaliplatin pharmacokinetics. (2) Neurotoxicity is the dose-limiting toxicity for oxaliplatin and is likely to be the most serious impediment to its widespread clinical acceptance. Thus, the applicant proposes to: a) determine the dose of oxaliplatin which causes significant neurotoxicity by behavioral and morphometric assays in Wistar rats; b) test the effect of the protective agents ORG2766, WR-2721 and glutathione on oxaliplatin neurotoxicity in this model; c) test the effect of the same agents on oxaliplatin efficacy against the Walker 256 tumor. These data should allow selection of those protective agents which offer the greatest protection against oxaliplatin neurotoxicity with the least alteration of its efficacy. (3) The characteristics of Pt compounds which determine the extent of their neurotoxicity are not well defined. The applicant plans to compare the neurotoxicity of cisplatin, ormaplatin, oxaliplatin and related Pt compounds in vivo and with cultures of dorsal root ganglia in vitro. These experiments should provide a: (a) quantitative comparison of the neurotoxicity of all three Pt drugs; (b) working model for which characteristics of these Pt compounds (hydrophobicity, carrier ligand, isomer of carrier ligand, or oxidation state of Pt) are most closely related to their neurotoxicity; and (c) rationale for design of Pt compounds with reduced neurotoxic potential.

描述：（申请人摘要）奥沙利铂（1-反式）1,2- 二氨基环己烷草酸铂(II)是第二代铂在欧洲临床试验中显示出巨大前景的化合物因为它对顺铂耐药的肿瘤有效。 (1) 的申请人已开发出用于解析和定量的 HPLC 技术主要的二氨基环己烷 (dach)-Pt 生物转化奥沙利铂。他计划研究其稳定性和机制草酸根在血浆中留下配体的置换和奥沙利铂的细胞内生物转化。这些研究将表征奥沙利铂激活的机制和动力学并为身份识别提供有价值的信息伴随临床研究中的生物转化产品和途径奥沙利铂的药代动力学。 (2)神经毒性是剂量限制性的奥沙利铂的毒性可能是最严重的障碍使其得到广泛的临床认可。因此，申请人建议： a) 确定奥沙利铂的剂量，该剂量会引起显着的通过 Wistar 大鼠的行为和形态测定测定的神经毒性； b) 测试保护剂 ORG2766、WR-2721 和谷胱甘肽对该模型中奥沙利铂的神经毒性的影响； c) 测试相同药物对奥沙利铂针对 Walker 256 疗效的影响瘤。这些数据应该允许选择那些保护剂提供针对奥沙利铂神经毒性的最大保护其功效变化最小。 (三)特点决定其神经毒性程度的 Pt 化合物不是定义明确。申请人计划比较神经毒性顺铂、奥马铂、奥沙利铂和相关铂化合物的体内和体外培养背根神经节。这些实验应该提供： (a) 所有神经毒性的定量比较三种铂类药物； (b) 工作模型，这些 Pt 的特性化合物（疏水性、载体配体、载体配体的异构体，或 Pt的氧化态与其神经毒性关系最为密切； (c) 设计神经毒性降低的 Pt 化合物的基本原理潜在的。