DEVELOP ASSAY TO QUANT PLAT-DNA ADDUCTS & PREDICT RESPONSE TO CHEMOTHERA

开发定量平台 DNA 加合物的检测方法

• 批准号: 8171688
• 负责人: Paul Thomas Henderson
• 金额: $ 16.99万
• 依托单位: UNIVERSITY OF CALIF-LAWRNC LVRMR NAT LAB
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171688
• 关键词: Address; Antineoplastic Agents; Biological Assay; Cancer Patient; Carboplatin; Cell Death; Cells; Cisplatin; Computer Retrieval of Information on Scientific Projects Database; Cytolysis; DNA; DNA Adducts; DNA Repair; Detection; Dose; Drug Kinetics; Drug resistance; Escherichia coli; Funding; Goals; Grant; Human; Incubated; Individual; Institution; Label; Malignant neoplasm of urinary bladder; Measures; Methods; Outcome; Patients; Pharmaceutical Preparations; Platinum; Radioactive; Research; Research Personnel; Resources; Source; Technology; Time; United States National Institutes of Health; adduct; base; cancer cell; in vivo; oxaliplatin; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. AMS will be applied to measuring the platinum-DNA adducts for drug pharmacokinetics. In spite of the importance of platinum-based anticancer drugs (cisplatin, carboplatin and oxaliplatin), their mechanisms of action, repair of damaged DNA and pharmacokinetics are unclear because of the detection limit of conventional methods (conventional methods have failed in quantifying Pt-DNA adducts with cells incubated with a pharmacological dose of the anticancer agent, which is the reason we need the sensitivity of AMS). In order to address these important issues, 14C-labeled carboplatin and oxaliplatin will be administered to E. coli, human cells, and bladder cancer patients, which may overcome the previous detection limits even at sub-pharmacological doses. The goals are to use AMS to elucidate their in vivo mechanism of action, to correlate Pt-DNA adduct level with cell death using a variety of human cancer cells, to determine the pharmacokinetics of the patients dosed with 14C-labeled carboplatin and oxaliplatin, and to ultimately correlate the phamacokinetic results to individual outcome (patient survival). Experimentally, after dosing a number of human cancer cells or cancer patients with radioactive platinum-based anticancer drugs, cell lysis and extracted platinated DNA will be measured by AMS. These 'real-time pharmacokinetics' will allow determination of which cancer patients will benefit from platinum treatment and which will be resistant to the drugs. Because of the high sensitivity, AMS is the very best technology for realizing these challenging goals.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 AMS将用于测量用于药物药物的铂DNA加合物。尽管基于铂的抗癌药（顺铂，卡铂和奥沙利铂）的重要性，但它们的作用机制，损坏的DNA和药代动力学的修复机制尚不清楚，因为常规方法的检测极限（传统方法都无法与PTNNA添加的质量加入，因为PT-DNA均与PT-DNA加入有关，而PT-DNA均与PT-DNA加入有关，而PT-DNA的质量构成了PT-DNA的作用，而PT-DNA则在pt-DNA中取代了PT-DNA，并且是在PT-DNA中加入的，而PT-DNA的作用是在PT-DNA中添加了pt-DNA的作用。 AMS的灵敏度）。为了解决这些重要问题，将对大肠杆菌，人类细胞和膀胱癌患者进行14C标记的卡铂和奥沙利铂，这些患者即使在亚药理学剂量下也可以克服先前的检测限制。目标是利用AMS阐明其体内作用机理，使用各种人类癌细胞将PT-DNA加合物与细胞死亡相关联，以确定用14C标记的卡泊蛋白和Oxaliptin的患者的药代动力学，并最终使Phamacokokokokokokokokokokokokokokokokokokinetic conter cormation Survice cotive conterscomecomection（患者）。在实验上，在用放射性铂基药物给予许多人类癌细胞或癌细胞患者后，将通过AMS测量细胞裂解和提取的铂为DNA。这些“实时药代动力学”将允许确定哪些癌症患者将从铂治疗中受益，哪些将对药物有抵抗力。由于敏感性很高，AMS是实现这些具有挑战性目标的最佳技术。