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）为各种生物疾病提供了独特的非侵入性体内定量。用F-18标记的氟脱氧葡萄糖（FDG）的PET成像已经显示出巨大的希望，成为许多癌症的诊断和分期的强大的独特的临床工具，特别是当它与计算机断层扫描（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然没有得到很好的理解。为了进一步探索这一点，四种人非小细胞肺癌（NSCLC）细胞系（鳞状细胞癌、腺癌、大细胞癌和细支气管肺泡癌）将用悬浮液中的微载体固定。这种将细胞与其他控制因素分离的三维组织培养系统类似于分离的灌注心脏系统。时间活性曲线（TAC）将获得高时间分辨率的FDG摄取到细胞与两个外部γ探针的在线动态测量。将通过与转运和磷酸化步骤相关的动力学参数的房室模型进一步分析TAC。该提案的三个具体目标是：1.确定四种常见非小细胞肺癌的生长条件，以获得每克微载体固定化细胞的稳态，2。为了表征3-D组织培养系统中所有四种细胞类型的代谢和血液动力学参数（氧、葡萄糖、乳酸盐、CO2、pH、温度），3.研究FDG在所有四种细胞类型中的动力学和集总常数行为。由于葡萄糖转运蛋白和己糖激酶亚型的过度表达预计不会对所有癌症都是相同的，因此这四种NSCLC中的FDG动力学应表现出一定程度的差异摄取。从拟议的研究中获得的结果将为理解癌细胞中FDG动力学和识别新的非侵入性手段来探测生物疾病提供基础。同样的实验装置也可以用于许多其他类型的细胞，以探测生物疾病与PET或SPECT配体。选择非小细胞肺癌中的FDG动力学仅是为了通过将问题与PET成像中完善的临床程序相关联来证明其潜在效用。因此，长期的目标是开发一个多功能的实验装置，结合了三维组织培养系统与外部伽马探针的开发和评价放射性药物。

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.