Labeled Thymidine-Development as A PET Imaging Agent

描述(由申请人提供)： 我们致力于开发胸腺嘧啶核苷及其类似物，用于正电子发射断层扫描(PET)和癌症评估。在我们开发的不同的类似物中，Flt(3‘-脱氧-3’-氟代胸苷)被发现是最有前途的类似物之一。FLT提供高对比度的肿瘤图像，背景低，特别是在胸腔内。我们已经建立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(TK1)的作用以其磷酸化形式保留在细胞中。虽然很少的Flt被掺入DNA，但其他人已经证明，它的摄取与非小细胞肺癌(NSCLC)和淋巴瘤患者的增殖有关，这是由Ki67测量的。还需要进一步的工作来开发用于癌症评估的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在非小细胞肺癌治疗评估中的摄取情况，具体如下：1)可切除的局部晚期疾病(ILIA期)的患者将接受放射和顺铂/依托泊苷治疗。这些患者将在治疗前和至少在4500 cgy的放射治疗结束时，考虑进行手术时进行FLT成像。在手术中取出的样本将被分析以验证成像。[F-18]同时进行脱氧葡萄糖(FDG)显像，以供比较。成像结果将与最终的临床结果进行比较，包括进展时间和生存时间。2)。转移性疾病(IV期)患者将在卡铂/紫杉醇治疗1个周期和2个周期之前和之后进行研究，使用Flt和FDG。Flt保留的变化也将在培养中进行检测，以将体内看到的变化与增殖和胸苷激酶表达的变化相关联。3)最后，我们将检查接受靶向药物、表皮生长因子受体抑制剂吉非替尼(易瑞沙，ZD1839)和环氧合酶2(塞来昔布)联合治疗的患者Flt的保留情况。我们试图确定在进行大型III期试验之前，PET是否可以提供早期的疗效测量。综上所述，我们的建议旨在开发用于肺癌治疗评估的Flt成像。我们的最终目标是证明这种方法在评估实验性和常规临床治疗方面都是有用的。

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.