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.
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