PET IMAGING OF DRUG KINETICS AND PATHWAYS

正电子发射断层扫描（PET）允许人们在体内和无创地测量肿瘤代谢。根据所使用的示踪剂，可以测量许多代谢途径。通过标记化疗药物与PET一起使用，可以测量它们在体内的分布。除了提供有关特定药物的药效学信息外，保留在感兴趣的生化途径中的药物也可用于评估肿瘤中这些途径在使用其他药物治疗之前和治疗后的活性。为了验证这一范例，我们选择研究[F-18] FAU{1-（2'-脱氧-2'-氟- β -d -阿拉伯糖脲基）-尿嘧啶}在PET中的应用。这种化合物正在我们的机构进入I期试验。它是一种抗代谢物，经胸苷激酶1 （TK）和胸苷酸合成酶（TS）的顺序激活后并入DNA。我们正在开发[F-18]FAU的合成，以测量药物保留并使用它来评估其在该途径中的动力学。接受未标记FAU治疗的患者将在治疗前进行成像，然后在治疗时通过混合标记药物和治疗药物重新研究。这将使我们能够计算输送到肿瘤和正常组织的药物量。我们将把PET结果与肿瘤标本上的TK和TS水平进行比较。我们将构建[F-18]FAU代谢的动力学模型，正如我们对胸苷所做的那样，以测量通过该途径的通量。为了确定TK和TS对FAU保留的相对贡献，我们还将研究另一种示踪剂[F-18]FLT（3'-脱氧-3'-氟胸苷），它在TK磷酸化后被特异性保留。用两种示踪剂对患者进行成像将使我们能够测量这一途径的每一步。TS的测量尤其重要，因为初步研究表明肿瘤中TS水平升高可能导致5FU耐药。此外，TS是许多新的抗肿瘤药物的靶点。虽然[F-18]FAU可用于测量药物治疗剂量的摄取和TK和TS途径的活性，但它也可作为细胞增殖的相对测量。TK和TS在细胞中受到密切调控，当细胞进入DNA合成阶段时，它们的活性增加约10倍。因此，FAU和FLT与PET一起使用时，可以提供肿瘤生长和治疗反应的相对指标。我们提出的[F-18]FAU与PET的研究将提供这种新型治疗剂的生物分布信息，并可能为肿瘤TS活性和增殖成像提供一种方法。

Positron emission tomography (PET) allows one to measure tumor metabolism in vivo and non-invasively. Depending on the tracer employed one can measure a number of metabolic pathways. By labeling chemotherapeutic agents for use with PET one can measure their distribution in vivo. In addition to providing information regarding a specific drug's pharmacodynamics, agents that are retained in biochemical pathways of interest may also be useful in assessing the activity of these pathways in tumors prior to and in response to treatment with other agents. To test this paradigm we have chosen to study [F-18] FAU {1-(2'-deoxy-2'- fluoro-beta-D-arabinofuranosyl)-uracil} for use in PET. This compound is entering phase I trials at our institution. It is an antimetabolite that is incorporated into DNA after sequential activation by thymidine kinase 1 (TK) and thymidylate synthase (TS). We are developing the synthesis of [F-18]FAU to measure the drug retention and use it to assess its kinetics in this pathway. Patients being treated with unlabeled FAU, will be imaged prior to treatment and then re-studied at the time of treatment, by mixing the labeled and therapeutic drugs. This will allow us to calculate the quantity of drug delivered to tumors and normal tissues. We will compare PET results to measurements of TK and TS levels made on tumor specimens. We will construct kinetic models of [F-18]FAU metabolism, as we have done for thymidine, in order to measure the flux through this pathway. To determine the relative contributions of TK and TS to FAU retention we will also study another tracer, [F-18]FLT (3'- deoxy-3'-fluorothymidine), that is specifically retained after phosphorylation by TK. Imaging patients with both tracers will allow us to measure each step in this pathway. The measurement of TS is of particular importance, since preliminary studies show that increased TS levels in tumors may result in 5FU resistance. Furthermore TS is the target of a number of new antineoplastic agents. While [F-18]FAU may find use in measuring the uptake of the therapeutic doses of the drug and activity in the TK and TS pathways, it may also serve as a relative measure of cellular proliferation. Both TK and TS are closely regulated in cells and their activities increase about 10 fold as cells enter the DNA synthetic phase. As such, FAU and FLT when used with PET may provide relative measures of tumor growth and response to therapy. Our proposed study of [F-18]FAU with PET will provide information on the biodistribution of this new therapeutic agent and may provide a way to image tumor TS activity and proliferation.