title: Gemcitabine Mechanism of Action Confounds Early Assessment of Treatment Response by 3'-Deoxy-3'-[18F]Fluorothymidine in Preclinical Models of Lung Cancer.
abstract: 3'-Deoxy-3'-[18F]fluorothymidine positron emission tomography ([18F]FLT-PET) and diffusion-weighted MRI (DW-MRI) are promising approaches to monitor tumor therapy response. Here, we employed these two imaging modalities to evaluate the response of lung carcinoma xenografts in mice after gemcitabine therapy. Caliper measurements revealed that H1975 xenografts responded to gemcitabine treatment, whereas A549 growth was not affected. In both tumor models, uptake of [18F]FLT was significantly reduced 6 hours after drug administration. On the basis of the gemcitabine concentration and [18F]FLT excretion measured, this was presumably related to a direct competition of gemcitabine with the radiotracer for cellular uptake. On day 1 after therapy, [18F]FLT uptake was increased in both models, which was correlated with thymidine kinase 1 (TK1) expression. Two and 3 days after drug administration, [18F]FLT uptake as well as TK1 and Ki67 expression were unchanged. A reduction in [18F]FLT in the responsive H1975 xenografts could only be noted on day 5 of therapy. Changes in ADCmeanin A549 xenografts 1 or 2 days after gemcitabine did not seem to be of therapy-related biological relevance as they were not related to cell death (assessed by caspase-3 IHC and cellular density) or tumor therapy response. Taken together, in these models, early changes of [18F]FLT uptake in tumors reflected mechanisms, such as competing gemcitabine uptake or gemcitabine-induced thymidylate synthase inhibition, and only reflected growth-inhibitory effects at a later time point. Hence, the time point for [18F]FLT-PET imaging of tumor response to gemcitabine is of crucial importance. Cancer Res; 76(24); 7096-105. ©2016 AACR.
authors: European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms-Universität (WWU) Münster, Münster, Germany.
authors: Sonja
authors: S
authors: Schelhaas
authors: European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms-Universität (WWU) Münster, Münster, Germany.
authors: Annelena
authors: A
authors: Held
authors: Department of Clinical Radiology, University Hospital of Münster, Münster, Germany.
authors: Lydia
authors: L
authors: Wachsmuth
authors: European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms-Universität (WWU) Münster, Münster, Germany.
authors: Sven
authors: S
authors: Hermann
authors: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors: Davina J
authors: DJ
authors: Honess
authors: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors: Kathrin
authors: K
authors: Heinzmann
authors: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors: Donna-Michelle
authors: DM
authors: Smith
authors: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors: John R
authors: JR
authors: Griffiths
authors: Department of Clinical Radiology, University Hospital of Münster, Münster, Germany.
authors: Cornelius
authors: C
authors: Faber
authors: European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms-Universität (WWU) Münster, Münster, Germany. ahjacobs@uni-muenster.de.|Department of Geriatric Medicine, Johanniter Hospital, Bonn, Germany.
authors: Andreas H
authors: AH
authors: Jacobs
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015224:Dideoxynucleosides; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods*; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000000981:diagnostic imaging*; D051379:Mice; D008819:Mice, Nude; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D015224:Dideoxynucleosides; D019275:Radiopharmaceuticals; D003841:Deoxycytidine; C002854:alovudine; D000093542:Gemcitabine