RT Journal Article SR Electronic T1 Variability of Proliferation and Diffusion in Different Lung Cancer Models as Measured by 3′-Deoxy-3′-18F-Fluorothymidine PET and Diffusion-Weighted MR Imaging JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 983 OP 988 DO 10.2967/jnumed.113.133348 VO 55 IS 6 A1 Sonja Schelhaas A1 Lydia Wachsmuth A1 Thomas Viel A1 Davina J. Honess A1 Kathrin Heinzmann A1 Donna-Michelle Smith A1 Sven Hermann A1 Stefan Wagner A1 Michael T. Kuhlmann A1 Carsten Müller-Tidow A1 Klaus Kopka A1 Otmar Schober A1 Michael Schäfers A1 Richard Schneider A1 Eric O. Aboagye A1 John Griffiths A1 Cornelius Faber A1 Andreas H. Jacobs YR 2014 UL http://jnm.snmjournals.org/content/55/6/983.abstract AB Molecular imaging allows the noninvasive assessment of cancer progression and response to therapy. The aim of this study was to investigate molecular and cellular determinants of 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) PET and diffusion-weighted (DW) MR imaging in lung carcinoma xenografts. Methods: Four lung cancer cell lines (A549, HTB56, EBC1, and H1975) were subcutaneously implanted in nude mice, and growth was followed by caliper measurements. Glucose uptake and tumor proliferation were determined by 18F-FDG and 18F-FLT PET, respectively. T2-weighted MR imaging was performed, and the apparent diffusion coefficient (ADC) was determined by DW MR imaging as an indicator of cell death. Imaging findings were correlated to histology with markers for tumor proliferation (Ki67, 5-bromo-2′-deoxyuridine [BrdU]) and cell death (caspase-3, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling). The expression of human equilibrative nucleoside transporter 1 (hENT1), thymidine kinase 1 (TK1), thymidylate synthase, and thymidine phosphorylase (TP) were analyzed by Western blot and immunohistochemistry. Thymidine levels were determined by liquid chromatography–mass spectrometry. Results: Xenografts varied with respect to in vivo growth rates. MR imaging and PET revealed intratumoral heterogeneities, which were confirmed by histology. 18F-FLT uptake differed significantly between tumor lines, with A549 and H1975 demonstrating the highest radiotracer accumulation (A549, 8.5 ± 3.2; HTB56, 4.4 ± 0.7; EBC1, 4.4 ± 1.2; and H1975, 12.1 ± 3.5 maximal percentage injected dose per milliliter). In contrast, differences in 18F-FDG uptake were only marginal. No clear relationship between 18F-FLT accumulation and immunohistochemical markers for tumor proliferation (Ki67, BrdU) as well as hENT1, TK1, or TS expression was detected. However, TP was highly expressed in A549 and H1975 xenografts, which was accompanied by low tumor thymidine concentrations, suggesting that tumor thymidine levels influence 18F-FLT uptake in the tumor models investigated. MR imaging revealed higher ADC values within proliferative regions of H1975 and A549 tumors than in HTB56 and EBC1. These ADC values were negatively correlated with cell density but not directly related to cell death. Conclusion: A direct relationship of 18F-FLT with proliferation or ADC with cell death might be complicated by the interplay of multiple processes at the cellular and physiologic levels in untreated tumors. This issue must be considered when using these imaging modalities in preclinical or clinical settings.