PET IMAGING OF DRUG KINETICS AND PATHWAYS

正电子发射断层扫描（PET）允许在体内和非侵入性地测量肿瘤代谢。 根据所采用的示踪剂，可以测量许多代谢途径。 通过标记与PET一起使用的化疗剂，可以测量它们在体内的分布。 除了提供关于特定药物的药效学的信息之外，保留在感兴趣的生化途径中的药剂也可用于评估在用其他药剂治疗之前和响应于用其他药剂治疗的肿瘤中这些途径的活性。 为了测试该范例，我们选择研究用于PET的[F-18] FAU {1-（2 '-脱氧-2'-氟-β-D-阿拉伯呋喃糖基）-尿嘧啶}。 这种化合物正在我们机构进行第一阶段试验。 它是一种抗代谢药，在胸苷激酶1（TK）和胸苷酸合成酶（TS）的顺序激活后掺入DNA中。 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进行重新研究。这将使我们能够计算输送到肿瘤和正常组织的药物量。 我们将比较PET结果与肿瘤标本上的TK和TS水平测量值。 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），其在TK磷酸化后特异性保留。 用这两种示踪剂对患者进行成像将使我们能够测量这一途径中的每一步。 TS的测量特别重要，因为初步研究表明肿瘤中TS水平的增加可能导致5 FU抗性。此外，TS是许多新的代理商的目标。 虽然[F-18]FAU可用于测量治疗剂量药物的摄取以及TK和TS途径中的活性，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节，当细胞进入DNA合成期时，它们的活性增加约10倍。 因此，FAU和FLT在与PET一起使用时可以提供肿瘤生长和对治疗反应的相对测量。 我们提出的[F-18]FAU与PET的研究将提供这种新的治疗剂的生物分布的信息，并可能提供一种方法来成像肿瘤TS活动和增殖。

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.