PET Proliferation Tracers

描述（由申请人提供）：我们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度以及该速度如何因治疗而改变。临床和临床前研究已经建立了胸腺嘧啶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，可以提供肿瘤对体内癌症治疗反应的信息。然而，问题仍然是使用哪种模拟，以及什么是最合适的图像分析方法。提出的工作将解决这些问题以及通常被忽视的肿瘤相关因素的作用，这些因素可能影响示踪剂测量的特异性。本研究的主要目的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-氟胸腺嘧啶）、FMAU（2'-氟-5-甲基-1-（_- d -2-阿拉伯-呋喃基）尿嘧啶）和胸腺嘧啶）摄取之间的关系是否可以通过以下改变来改变：(1)核苷转运体水平、(2)细胞周期检查点控制完整性、(3)新生核苷酸生物合成活性和(4)核苷酸外排转运体的存在。等基因细胞系将在生长和非生长条件下，在暴露于电离辐射、5-氟尿嘧啶或紫杉醇之前和之后，以及在体外和体内（肿瘤外植体）试验中进行研究。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和保留的不同影响。我们的目标是开发一种简化和临床可行的方法来量化FLT摄取，该方法基于FLT动力学的详细知识和影响动力学的因素，如肿瘤基因型和治疗方式。

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.