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Significance of GGT Expression in Tumors

GGT 在肿瘤中表达的意义

基本信息

批准号：
7369786
负责人：
MARIE H HANIGAN
金额：
$ 23.09万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-08-01 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7369786
关键词：
AA Spectrophotometry Abbreviations Acetylcysteine Alkenes Aminooxyacetic Acid Aspartate Binding Binding Proteins Biological Assay Cell Culture System Cell Line Cells Cisplatin Cysteine Cysteine Metabolism Pathway Data Enzymes Family Family suidae Folch-Pi apoprotein Funding Gamma-glutamyl transferase Glutathione Glutathione S-Transferase Goals Grant Hanks Balanced Salt Solution High Pressure Liquid Chromatography Human In Vitro Interphase Cell Kidney Lasers Lead Liver Location Mass Spectrum Analysis Metabolic Pathway Metabolism Mitochondrial Aspartate Aminotransferase Molecular Monitor Mus Myelin Proteolipid Protein Nephrotoxic Osmolar Concentration Parents Pharmaceutical Preparations Physiological Platinum Protein Binding Proteins Pyridoxal Phosphate RNA Interference Reaction Research Research Personnel Resistance Role S-alkylcysteine lyase Small Interfering RNA Sodium Sodium Chloride Solutions Sulfhydryl Compounds Testing Time Toxic effect Toxin Transfection Tubular formation Work base biological adaptation to stress cell killing chemotherapy cysteinylglycine extracellular glutamine - phenylpyruvate transaminase in vivo inhibitor/antagonist ionization kidney cell killings mitochondrial heat shock protein 70 neoplastic cell nephrotoxicity ovarian neoplasm protective effect research study resistance mechanism response tumor

项目摘要

DESCRIPTION (provided by applicant): Cisplatin is a potent chemotherapy drug and a nephrotoxin. The studies funded by this grant have revealed that the enzyme gamma-glutamyl transpeptidase is essential for the nephrotoxicity of cisplatin, but induces resistance to cisplatin in rapidly growing tumor cells. These data have led to the discovery that cisplatin is metabolized to a nephrotoxin via a platinum-glutathione conjugate. This is the first demonstration that cisplatin can undergo enzymatic activation to a metabolite that is more toxic than the parent compound. Our hypothesis is that cisplatin kills the non-dividing cells in the kidney by a mechanism that is distinct from the mechanism by which it kills the dividing tumor cells. This renewal application has three specific aims. The first is to identify the glutathione-S-transferases (GSTs) that catalyze the formation of the nephrotoxic platinum-GSH conjugate of cisplatin. An HPLC assay will be used to identify and monitor the purification of GSTs that catalyze the formation of the nephrotoxic platinum-GSH conjugate. A combination of siRNA and transfection studies will be done to confirm the role of the GST in cisplatin nephrotoxicity. Expression of GSTs in tumors has been associated with resistance to cisplatin. The resistance may be due to their ability to serve as a binding protein. GSTs that bind cisplatin will also be identified. The second specific aim is to identify the renal enzyme that catalyzes the metabolism of the platinum-cysteine conjugate to a toxin. In vivo and in vitro studies have shown that a pyridoxal 5'- phosphate-dependent enzyme catalyzes this reaction. The third specific aim is to identify the mechanism by which the sodium stress response blocks cisplatin nephrotoxicity. Sodium chloride is used clinically to reduce cisplatin nephrotoxicity. The mechanism of this protective effect is not known. A cell culture system will be used to investigate the molecular basis of this response. Tumor cells will be analyzed to determine if the sodium stress response is constitutively expressed in cisplatin-resistant cells. Cisplatin is one of the most commonly used chemotherapy drugs. The goal of this research is to understand the molecular mechanisms by which cisplatin kills cells and the mechanism by which cells become resistant to cisplatin.

描述（由申请人提供）：顺铂是一种强效化疗药物和肾毒素。由该基金资助的研究表明，γ-谷氨酰转肽酶对顺铂的肾毒性至关重要，但在快速生长的肿瘤细胞中诱导对顺铂的耐药性。这些数据导致发现顺铂通过铂-谷胱甘肽缀合物代谢为肾毒素。这是第一次证明顺铂可以通过酶活化产生比母体化合物毒性更大的代谢物。我们的假设是，顺铂通过一种与其杀死分裂肿瘤细胞的机制不同的机制杀死肾脏中的非分裂细胞。这次更新申请有三个具体目标。第一个是确定谷胱甘肽-S-转移酶（GST），催化顺铂的肾毒性铂-GSH结合物的形成。将使用HPLC测定法鉴别和监测催化肾毒性铂-GSH结合物形成的GST的纯化。将进行siRNA和转染研究的组合以确认GST在顺铂肾毒性中的作用。GST在肿瘤中的表达与顺铂耐药相关。这种抗性可能是由于它们作为结合蛋白的能力。还将鉴定结合顺铂的GST。第二个具体目标是鉴定催化铂-半胱氨酸结合物代谢为毒素的肾酶。体内和体外研究表明，吡哆醛5 '-磷酸依赖性酶催化该反应。第三个具体目标是确定钠应激反应阻断顺铂肾毒性的机制。氯化钠在临床上用于减少顺铂的肾毒性。这种保护作用的机制尚不清楚。将使用细胞培养系统研究这种反应的分子基础。将分析肿瘤细胞，以确定钠应激反应是否在顺铂耐药细胞中组成型表达。顺铂是最常用的化疗药物之一。本研究的目的是了解顺铂杀死细胞的分子机制以及细胞对顺铂产生耐药性的机制。

项目成果

期刊论文数量（36）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Human germ cell tumours: expression of gamma-glutamyl transpeptidase and sensitivity to cisplatin.

人类生殖细胞肿瘤：γ-谷氨酰转肽酶的表达和对顺铂的敏感性。

DOI：
10.1038/sj.bjc.6690653
发表时间：
1999
期刊：
British journal of cancer
影响因子：
8.8
作者：
Hanigan,MH;FriersonJr,HF;Abeler,VM;Kaern,J;TaylorJr,PT
通讯作者：
TaylorJr,PT

Cisplatin-induced toxicity is associated with platinum deposition in mouse kidney mitochondria in vivo and with selective inactivation of the alpha-ketoglutarate dehydrogenase complex in LLC-PK1 cells.

顺铂诱导的毒性与体内小鼠肾线粒体中的铂沉积以及 LLC-PK1 细胞中 α-酮戊二酸脱氢酶复合物的选择性失活有关。

DOI：
10.1021/bi060027g
发表时间：
2006
期刊：
Biochemistry
影响因子：
2.9
作者：
Zhang,Lei;Cooper,ArthurJL;Krasnikov,BorisF;Xu,Hui;Bubber,Parvesh;Pinto,JohnT;Gibson,GaryE;Hanigan,MarieH
通讯作者：
Hanigan,MarieH

Expression of gamma-glutamyl transpeptidase in stage III and IV ovarian surface epithelial carcinomas does not alter response to primary cisplatin-based chemotherapy.

III 期和 IV 期卵巢表面上皮癌中 γ-谷氨酰转肽酶的表达不会改变对基于顺铂的主要化疗的反应。