LABELED THYMIDINE--DEVELOPMENT AS A PET IMAGING AGENT

使用适当的代谢示踪剂，正电子发射断层扫描（PET）能够测量肿瘤增殖，潜在地提供有关治疗反应的关键信息。虽然[C-11]胸苷可以用于这项任务，但由于其半衰期短和体内分解代谢迅速，其常规使用变得复杂。为了克服这些困难，本提案将重点关注[F-18]FLT（3'-脱氧-3'-氟胸苷），它已被证明可以提供肿瘤和增殖组织的高质量图像。FLT几乎没有退化，使用寿命较长的示踪剂F-18。FLT通过胸苷激酶1 （TK）的磷酸化作用被困在快速生长的肿瘤中，这种酶在细胞进入DNA合成阶段时增加约10倍。本建议旨在进一步简化FLT的使用，更好地理解导致其保留的变量，并使用它来衡量对治疗的反应。具体目标包括：1)通过更快速、自动化的合成来改善FLT的使用。为了协助肝脏肿瘤的成像，在肝脏中，FLT被葡萄糖醛酸化捕获，将进一步研究使用probenecid来阻止摄取。2)将研究不同肿瘤类型以及炎性病变的FLT成像，以探索其有用的条件范围。3)为了更充分地了解影响FLT图像的因素，将研究不同的定量方法，包括动力学建模。这些结果将与活检标本上的TK和其他肿瘤代谢标志物的测量结果进行比较。4)最后，FLT最重要的测试将包括证明其在接受标准细胞毒治疗和旨在延缓肿瘤生长的新细胞抑制剂治疗的患者中作为肿瘤对治疗反应的早期测量。这些新的细胞抑制药物，如酪氨酸激酶和血管生成抑制剂，很难用传统的解剖成像来评估，因为肿瘤不会缩小。代谢成像可能提供唯一可行的方法来确定这些药物是否有效，除非进行大规模的III期试验。在没有反应的中间标记物的情况下，特别难以确定这类药物的最佳剂量和时间表。这些研究将验证这样一种假设，即PET增殖成像将提供评估此类药物的最佳方法。综上所述，我们实验室之前的工作已经开发出一种新颖且相对直接的肿瘤增殖成像方法。本提案旨在进一步了解量化、解释和临床测试这种方法以测量治疗反应的最佳方法。

With the appropriate metabolic tracers positron emission tomography (PET) is able to measure tumor proliferation, potentially providing critical information about treatment response. While [C-11]thymidine can be employed in this task, its routine use is complicated by its short half-life and rapid in vivo catabolism. To overcome these difficulties this proposal will focus on [F-18]FLT (3'-deoxy-3'-fluorothymidine), which has been demonstrated to provide high quality images of tumors and proliferating tissues. FLT undergoes little degradation and employs F-18, a longer lived tracer. FLT is trapped in rapidly growing tumors by phosphorylation by thymidine kinase 1 (TK), an enzyme which increases about 10 fold as the cell enters the DNA synthetic phase. This proposal seeks to further simplify the use of FLT, better understand the variables that lead to its retention, and use it to measure response to therapy. The specific aims include: 1) To improve the use of FLT through a more rapid, automated synthesis. To assist in imaging tumors in the liver, where FLT is trapped by glucuronidation, further studies will be done to block uptake using probenecid. 2) Imaging with FLT of different tumor types as well as inflammatory lesions will be studied to explore the range of conditions where it will be useful. 3) To more fully understand the factors contributing to images of FLT, different quantitative approaches will be studied including kinetic modeling. These results will be compared to measurements of TK and other markers of tumor metabolism made on biopsy specimens. 4) Finally, the most important test of FLT will involve demonstrating its use as an early measure of tumor response to therapy in patients undergoing both standard cytotoxic therapy as well as new cytostatic treatments that are designed to delay tumor growth. These new cytostatic drugs, such as tyrosine kinase and angiogenesis inhibitors, an are difficult to assess using conventional anatomic imaging, since tumor shrinkage is not expected. Metabolic imaging may provide the only feasible way to determine if such agents are efficacious short of large phase III trials. It is particularly hard to determine the optimum dose and schedule of such drugs without an intermediate marker of response. These studies will test the hypothesis that PET imaging of proliferation will provide the best way to asses such agents. In summary, previous work in our laboratory has developed a novel and relatively straightforward way to image tumor proliferation. This proposal seeks to further understand the best way to quantitate, interpret, and clinically test this approach to measure treatment response.