Labeled Thymidine -- Development as A PET Imaging Agent

描述（由申请人提供）： 我们致力于开发胸苷及其类似物用于正电子发射断层扫描（PET）和癌症评估。在我们开发的不同类似物中，FLT（3 '-脱氧-3'-氟胸苷）被认为是最有前途的类似物之一。FLT提供高对比度肿瘤图像，并且具有低背景，特别是在胸腔内。我们已经产生了其保留的动力学模型，并在活检标本上进行了验证。FLT主要通过胸苷激酶（TK 1）的作用以磷酸化形式保留在细胞中。虽然很少FLT被掺入DNA，但其他人已经证明其摄取与非小细胞肺癌（NSCLC）和淋巴瘤患者的增殖相关，如通过ki 67测量的。需要进一步的工作来开发用于评估癌症的FLT，并将其与FDG进行比较。为了开发和测试这些用途，我们将研究FLT在NSCLC治疗评价中的摄取，如下：1）可切除的局部晚期疾病（伊利亚期）患者将接受放疗和顺铂/依托泊苷治疗。这些患者将在治疗前和至少在完成4500 CGy放射治疗时（考虑手术时）接受FLT成像。将对手术时取出的标本进行分析，以验证成像。同时进行[F-18]氟脱氧葡萄糖（FDG）成像以进行比较。将影像学结果与最终临床结果（包括至进展时间和生存期）进行比较。2）。转移性疾病（IV期）患者将在使用FLT和FDG进行卡铂/紫杉醇治疗的1个和2个周期之前和之后进行研究。还将在培养物中检查FLT保留的变化，以将体内观察到的变化与增殖和胸苷激酶表达的变化相关联。3)最后，我们将检查接受联合靶向药物治疗的患者的FLT保留情况;表皮生长因子受体抑制剂吉非替尼（易瑞沙，ZD 1839）和环氧合酶2（塞来昔布）。我们试图确定PET是否可以在进行大型III期试验之前提供早期疗效测量。总之，我们的建议旨在开发FLT成像用于评估肺癌治疗。我们的最终目标是证明这种方法在评估实验和常规临床治疗中是有用的。

DESCRIPTION (provided by applicant): We have worked to develop thymidine and its analogs for use in positron emission tomography (PET) and the evaluation of cancer. Of the different analogs that we have developed FLT (3'-deoxy-3'-fluorothymidine) has been found to be one of the most promising. FLT provides high contrast tumor images and has a low background particularly within the thorax. We have produced kinetic models of its retention and validated them on biopsy specimens. FLT is retained in cells primarily in its phosphorylated form by the action of thymidine kinase (TK1). While little FLT is incorporated into DNA, its uptake has been shown by others to correlate with proliferation in patients with non-small cell lung cancer (NSCLC) and lymphoma as measured by ki67. Further work is needed to develop FLT for use in the assessment of cancer and compare it to FDG. To develop and test these uses we will study the uptake of FLT in the evaluation of NSCLC treatment as follows: 1) Patients with resectable, locally advanced disease (stage IlIA) will be treated with radiation and cisplatin/etoposide. Such patients will be imaged with FLT prior to therapy and at least at the completion of 4500 CGy of radiation treatment, when they are being considered for surgery. Specimens removed at surgery will be analyzed to validate the imaging. [F-18] fluorodeoxyglucose (FDG) imaging will also be done at concurrently for comparision. Imaging results will be compared to the ultimate clinical results including time to progression and survival. 2). Patients with metastatic disease (stage IV) will be studied before and after one and two cycles of therapy with carboplatin/paclitaxel using both FLT and FDG. Changes in FLT retention will also be examined in culture, to correlate changes seen in vivo with changes in proliferation and thymidine kinase expression. 3) Finally we will examine the retention of FLT in patients undergoing therapy that combines targeted agents; inhibitors of epidermal growth factor receptor gefitinib (Iressa, ZD1839) and cyclooxygenase 2 (celecoxib). We seek to determine if PET can provide an early measure of efficacy before conducting large phase III trials. In summary, our proposal seeks to develop FLT imaging for use in the evaluation of lung cancer treatment. Our ultimate goal is to demonstrate that this approach is useful in evaluating both experimental and routine clinical treatment.