PET Proliferation Tracers

PET 增殖示踪剂

• 批准号: 7585290
• 负责人: JEFFREY L. SCHWARTZ
• 金额: $ 36.69万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7585290
• 关键词: 2' -Deoxythymidine; 2' -fluoro-5-methylarabinosyluracil; A549; Accounting; Address; Adenocarcinoma Cell; Affect; Aftercare; Automobile Driving; Biological Assay; Brain; Breast; Cell Cycle; Cell Cycle Checkpoint; Cell Line; Cell Proliferation; Cell physiology; Cells; Clinical; Cytostatics; Cytotoxic agent; DNA-Directed DNA Polymerase; Elements; Evaluation Studies; Exposure to; Fluorouracil; Genetic Transcription; Genotype; Goals; Growth; Human; Image; Image Analysis; In Vitro; Ionizing radiation; Kinetics; Knowledge; Laboratories; Measurement; Measures; Metabolism; Modality; Modeling; Mus; Nucleoside Transporter; Nucleosides; Nucleotidases; Nucleotide Biosynthesis; Nucleotides; Paclitaxel; Pathway interactions; Patients; Phase; Positron-Emission Tomography; Proliferating; Prostate; Radiation; Reporting; Role; Specificity; TK1 gene; Testing; Thymidine; Tracer; Tumor Cell Line; Uracil; Validation; Variant; Work; analog; base; cancer therapy; chemotherapy; colon cancer cell line; cytotoxic; enzyme activity; in vivo; irradiation; neoplastic cell; nucleotidase; nucleotide metabolism; pre-clinical; preclinical study; response; selective expression; thymidine kinase 1; tumor; uptake

DESCRIPTION (provided by applicant): There is great need for a quantitative imaging test that can be done serially and will report on the growth rate of a tumor and how that rate has been changed by treatment. Clinical and preclinical studies have established the potential of thymidine analogs as positron emission tomography (PET)-based measure of tumor cell proliferation that may provide information on tumor response to cancer therapy in vivo. However, questions remain as to which analog to use, and what would be the most appropriate approach to image analysis. The proposed work will address these questions as well as the usually overlooked role of tumor-associated factors that can influence the specificity of tracer measurements. The primary goal of this study is to quantify how variations in tumor-associated genotypes influence the relationship between tracer uptake and proliferation both in vitro and in vivo. The study will examine whether the relationship between tumor cell proliferation and the uptake of two nucleoside tracers, (FLT (3'- deoxy-3'-L-fluorothymidine), FMAU (2'-fluoro-5-methyl-1-(_-D-2-arabino-furanosyl) uracil), and thymidine), can be modified by alterations in (1) nucleoside transporter levels, (2) cell cycle checkpoint control integrity, (3) de novo nucleotide biosynthesis activity, and (4) the presence of nucleotide efflux transporters. Isogenic cell lines will be studied under both growth and nongrowth conditions, before and after exposure to ionizing radiation, 5-fluorouracil, or paclitaxel and with both in vitro and in vivo (tumor explant) assays. Dynamic kinetic-based PET analysis will be used in the in vivo studies in order to better understand differential effects on transport versus retention. Our goal is to develop a simplified and clinically feasible approach to quantify FLT uptake that is based upon detailed knowledge of FLT kinetics and factors, such as tumor genotype and treatment modality, that affect kinetics.

描述（由申请人提供）：非常需要一种可以连续进行的定量成像测试，该测试将报告肿瘤的生长速率以及该速率如何通过治疗而改变。临床和临床前研究已经确定了胸苷类似物作为基于正电子发射断层扫描（PET）的肿瘤细胞增殖测量的潜力，可以提供有关肿瘤对体内癌症治疗的反应的信息。然而，关于使用哪种模拟以及什么是最合适的图像分析方法仍然存在问题。拟议的工作将解决这些问题以及通常被忽视的可能影响示踪剂测量特异性的肿瘤相关因素的作用。本研究的主要目标是量化肿瘤相关基因型的变化如何影响体外和体内示踪剂摄取和增殖之间的关系。该研究将检查肿瘤细胞增殖与两种核苷示踪剂（FLT（3'-脱氧-3'-L-氟胸苷）、FMAU（2'-氟-5-甲基-1-(_-D-2-阿拉伯呋喃糖基）尿嘧啶）和胸苷）摄取之间的关系是否可以通过改变（1）核苷转运蛋白来改变 水平，（2）细胞周期检查点控制完整性，（3）从头核苷酸生物合成活性，以及（4）核苷酸流出转运蛋白的存在。将在生长和非生长条件下、暴露于电离辐射、5-氟尿嘧啶或紫杉醇之前和之后以及体外和体内（肿瘤外植体）测定对同基因细胞系进行研究。基于动态动力学的 PET 分析将用于体内研究，以便更好地了解对运输与保留的不同影响。我们的目标是开发一种简化且临床可行的方法来量化 FLT 摄取，该方法基于对 FLT 动力学和影响动力学的因素（例如肿瘤基因型和治疗方式）的详细了解。