Tumor FDG Kinetics in a 3-D Tissue Culture System

描述(由申请人提供)： 正电子发射断层扫描(PET)为多种生物疾病提供了体内非侵入性定量的独特性。F-18标记的氟脱氧葡萄糖(FDG)正电子发射体层摄影(PET)在多种肿瘤的诊断和分期中具有独特的临床应用前景，特别是当它与CT(CT)同时使用时。尽管如此，FDG作为癌细胞中葡萄糖代谢的放射性示踪剂的有效性仍未被很好地了解。为了进一步探索这一点，将用悬浮微载体固定化四种人非小细胞肺癌(NSCLC)系(鳞癌、腺癌、大细胞和细支气管肺泡)。这种3D组织培养系统将细胞与其他控制因素隔离开来，类似于隔离的灌流心脏系统。时间活动曲线(TAC)将通过两个外部伽马探针在线动态测量细胞摄取FDG而获得高时间分辨率。TAC将通过隔室模型进一步分析与运输和磷酸化步骤相关的动力学参数。这项建议的三个具体目标是：1.确定四种常见类型NSCLC的生长条件以获得每克微载体固定细胞的稳定状态；2.表征三维组织培养系统中所有四种细胞的代谢和血流动力学参数(氧、葡萄糖、乳酸、二氧化碳、pH、温度)；3.研究FDG动力学和所有四种细胞类型的集总恒定行为。由于葡萄糖转运体和己糖激酶亚型在所有肿瘤中的过度表达并不相同，FDG动力学在这四种非小细胞肺癌中应该表现出一定程度的不同摄取。这项拟议的研究结果将为了解癌细胞内FDG动力学和识别新的非侵入性手段探索生物疾病提供基础。同样的实验装置也可以用于许多其他类型的细胞，以探测具有PET或SPECT配体的生物疾病。选择FDG在NSCLC中的动力学只是为了证明它的潜在效用，因为它将问题与PET成像中成熟的临床程序联系起来。因此，长期目标是开发一种多功能的实验装置，将三维组织培养系统与外部伽马探测器相结合，用于放射性药物的开发和评估。

DESCRIPTION (provided by applicant): Positron Emission Tomography (PET) offers the uniqueness of non-invasive in vivo quantification for a variety of biological diseases. PET imaging with F-18 labeled fluorodeoxyglucose (FDG) has shown great promises to be a powerful unique clinical tool for the diagnosis and the staging of many carcinomas, especially when it is used simultaneously with Computed Tomography (CT). Nonetheless, the validity of FDG as a radiotracer for glucose metabolism in cancer cells is still not well understood. In order to explore this further, four human non-small cell lung cancer (NSCLC) lines (squamous, adenocarcinoma, large cell, and bronchioalveolar) will be immobilized with microcarriers in suspension. This 3-D tissue culture system where cells are isolated from other control factors is analogous to an isolated perfused heart system. Time activity curves (TAC) will be obtained in high temporal resolution by on-line dynamic measurement of FDG uptake into cells with two external gamma probes. The TAC will be further analyzed by a compartmental model for kinetic parameters associated with both the transport and phosphorylation steps. Three specific aims for this proposal are: 1. To determine the growth conditions to obtain a steady state of immobilized cells per gram microcarrier for four common types of NSCLCs, 2. To characterize the metabolic and hemodynamic parameters (oxygen, glucose, lactate, CO2, pH, temperature) for all four cell types in the 3-D tissue culture system, 3. To investigate FDG kinetics and the lumped constant behaviour in all four cell types. Since the overexpression of glucose transporter and hexokinase isoforms are not expected to be the same for all carcinomas, FDG kinetics in these four NSCLCs should demonstrate certain degree of differential uptakes. Results obtained from the proposed research will provide a basis for the understanding of FDG kinetics in cancer cells and the identification of new non-invasive means to probe biological diseases. The same experimental setup can also be used with many other types of cells to probe biological diseases with either PET or SPECT ligands. FDG kinetics in NSCLCs was chosen only to demonstrate its potential utility by relating problems to a well-established clinical procedure in PET imaging. Therefore the long-term objective is to develop a versatile experimental setup that combines a 3-D tissue culture system with external gamma probes for the development and the evaluation of radiopharmaceuticals.