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抑制剂伊立替康和托泊替康的排泄机制，我们研究了使用培养细胞的转运实验、使用大鼠的清除实验，并进行了药物转运蛋白的基因出现系统细胞（hOAT1细胞和hOAT3细胞）。结果表明，大鼠内脏器官中拓扑替康羟基酸形式（A-TPT）的清除率（CL）显示出较高的、内脏器官的特殊分布，顺序为肾≒肝>肺>小肠≒心脏>脑此外，在服用A-TPT时，未发现通过A的运输而导致的变化。与载体细胞相比，hOAT3细胞中的-TPT被显着促进。另外，对于A-TPT的转运，hOAT1细胞和hOAT3细胞均没有被促进。这些结果至少部分地参与了A-TPT的转变。HP100细胞是过氧化氢的耐受储备，过氧化氢是人类培养细胞HL-60中的活性氧种类之一，并且HL-60来源被用于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，提示过氧化氢参与了SN-38和拓扑替康的细胞凋亡，并提示了该途径的存在。激活过程如下：伊立替康DNA裂解→细胞H_20_2水平上升→线粒体损伤→caspase-3激活→细胞凋亡诱导。计划从细胞凋亡诱导的角度评估伊立替康和托泊替康对器官的损害另外，建立了器官损伤的检测方法，从药代动力学和药效学的角度验证了药物转运体在器官损伤中的作用。未来。