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Basic construction of individual administering design method based on clarification of excretion mechanism of topoisomerase I inhibitor

基于拓扑异构酶I抑制剂排泄机制的个体化给药设计方法的基本构建

基本信息

批准号：
18590139
负责人：
MIZUTANI Hideki
金额：
$ 2.44万
依托单位：
Kinjo Gakuin University (2007)Mie University (2006)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590139/
关键词：
drug transporter renal excretion of drug anti-cancer drug irinitecan topotecan apotosis

项目摘要

To clarify excretion mechanisms of irinotecan and topotecan, topoisomerase I inhibitors, we investigated the transportation experiment used the cultured cells, the clearance experiment used the rats, and the gene appearance system cell of the drug transporter (hOAT1 cell and hOAT3 cell) was executed. It was clarified that rat internal organs taking clearance (CL) of hydroxy acid form (A-TPT) of topotecan showed a high, internal organs peculiar distribution in order of kidney≒liver>lungs>small intestines≒heart>brain. In addition, the participation of an organic anion transportation system peculiar was suggested in taking of A-TPT. The change was not admitted in transportation in the hOAT1 cell though the transportation of A-TPT in the hOAT3 cell was remarkably promoted compared with the vector cell. In addition, neither the hOAT1 cell nor the hOAT3 cell were promoted as for the transportation of A-TPT. It was thought that OAT3 at least took part from these results in shift of A-TPT partially.The HP100 cell that was the tolerance stock of hydrogen peroxide that was one of the active oxygen species in human culture cell HL-60 and the HL-60 origin was used of the evaluation of the organ damage by irinotecan and topotecan ftom the viewpoint of the apoptosis induction. As a result, it was suggested that hydrogen peroxide take part in the apoptosis of SN-38 and topotecan, and was suggested the existence of the route in activation, as follows : DNA cleavage by irinotecan→rise in cellar level of H_20_2→mitochondria injury→activation of caspase-3→apoptosis induction.It is scheduled that the organ damage by irinotecan and topotecan is evaluated from the viewpoint of the apoptosis induction in addition, the detection method of the organ damage is established, and the role of the drug transporter in the organ damage is verified from the viewpoint of pharmacokinetics and pharmacodynamics in the future.

为了阐明拓扑异构酶I抑制剂伊立替康和拓扑替康的排泄机制，我们使用培养的细胞进行了转运实验，使用大鼠进行了清除实验，并进行了药物转运蛋白的基因出现系统细胞（hOAT 1细胞和hOAT 3细胞）。结果表明，大鼠内脏对拓扑替康羟基酸型（A-TPT）的清除率（CL）较高，内脏器官分布特殊，依次为肾>肝>肺>小肠>心>脑。此外，A-TPT的服用还可能有一个特殊的有机阴离子转运系统参与。与载体细胞相比，hOAT 3细胞中A-TPT的转运明显增强，但hOAT 1细胞中的转运没有发生变化。此外，对于A-TPT的转运，hOAT 1和hOAT 3细胞均未被促进。OAT 3至少部分参与了A-TPT的转移，本研究从诱导细胞凋亡的角度，以人培养细胞HL-60及其来源细胞HP 100为实验对象，评价了伊立替康和拓扑替康对器官的损伤作用。结果表明，过氧化氢参与了SN-38和拓扑替康的细胞凋亡，并提示存在如下激活途径：伊立替康对DNA的切割→细胞内H_2O_2水平升高→线粒体损伤→ caspase-3活化→细胞凋亡诱导。计划从细胞凋亡诱导的角度评价伊立替康和拓扑替康对器官的损伤。此外，建立了器官损伤的检测方法，今后将从药代动力学和药效学的角度验证药物转运蛋白在器官损伤中的作用。