PET IMAGING OF DRUG KINETICS AND PATHWAYS

正电子发射断层扫描(PET)可以在体内无创地测量肿瘤的代谢。根据所用示踪剂的不同，人们可以测量许多代谢途径。通过标记与PET一起使用的化疗药物，人们可以测量它们在体内的分布。除了提供有关特定药物药效学的信息外，保留在感兴趣的生化途径中的试剂也可能有助于在用其他药物治疗之前和在治疗后评估这些途径在肿瘤中的活性。为了测试这一范式，我们选择研究用于PET的[F-18]FAU{1-(2‘-脱氧-2’-氟-β-D-阿拉伯呋喃葡萄糖)-尿嘧啶}。这种化合物正在我们机构进入第一阶段试验。它是一种抗代谢物质，被胸苷激酶1(TK)和胸苷合成酶(TS)顺序激活后被结合到DNA中。我们正在开发合成[F-18]FAU来测量药物保留率，并用它来评估其在这一途径中的动力学。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向肿瘤和正常组织输送的药物的数量。我们将把PET的结果与肿瘤标本上的TK和TS水平的测量结果进行比较。我们将构建[F-18]FAU代谢的动力学模型，就像我们对胸苷所做的那样，以测量通过这一途径的通量。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)，它是TK磷酸化后特异性保留的。使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水平的增加可能会导致5FU耐药。此外，TS是许多新的抗肿瘤药物的靶点。虽然[F-18]FAU可以用来测量药物治疗剂量的吸收以及TK和TS通路中的活性，但它也可以作为细胞增殖的相对衡量标准。TK和TS在细胞内都受到密切的调控，当细胞进入DNA合成期时，它们的活性增加了大约10倍。因此，当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关指标。我们提出的[F-18]FAU与PET的研究将提供关于这种新治疗剂的生物分布的信息，并可能提供一种成像肿瘤TS活性和增殖的方法。

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.