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Gene Expression Patterns and Tumor Uptake of 18F-FDG, 18F-FLT, and 18F-FEC in PET/MRI of an Orthotopic Mouse Xenotransplantation Model of Pancreatic Cancer

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Gene Expression Patterns and Tumor Uptake of 18F-FDG, 18F-FLT, and 18F-FEC in PET/MRI of an Orthotopic Mouse Xenotransplantation Model of Pancreatic Cancer Journal of Nuclear Medicine, published on July 16, 2008 as doi:10.2967/jnumed.107.050021 Gene Expression Patterns and Tumor Uptake of 18F-FDG, 18F-FLT, and 18F-FEC in PET/MRI of an Orthotopic Mouse Xenotransplantation Model of Pancreatic Cancer Corinna von Forstner*1, Jan-Hendrik Egberts*2, Ole Ammerpohl2, Dagmara Niedzielska3, Ralph Buchert3, Pal Mikecz3, Udo Schumacher4, Kersten Peldschus5, Gerhard Adam5, Christian Pilarsky6, Robert Grutzmann6, Holger Kalthoff2, Eberhard Henze1, and Winfried Brenner3 1Department of Nuclear Medicine, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany; 2Department of General Surgery and Thoracic Surgery, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany; 3Department of Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 4Department of Anatomy II Experimental Morphology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 5Department of Diagnostic and Interventional Radiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and 6Department of Visceral, Thoracic, and Vascular Surgery, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany the highest and most consistent uptake in various human pan- Our aim was to use PET/MRI to evaluate and compare the uptake creatic tumor cell lines in SCID mice. The imaging results could of 18F-FDG, 3-deoxy-3-18F-fluorothymidine (18F-FLT), and 18F- be explained by gene expression patterns of membrane trans- fluorethylcholine (18F-FEC) in human pancreatic tumor cell lines porters and enzymes for tracer uptake and retention as mea- after xenotransplantation into SCID mice and to correlate tumor sured by gene array analysis and quantitative polymerase uptake with gene expression of membrane transporters and chain reaction in the respective cell lines. Thus, standard molec- rate-limiting enzymes for tracer uptake and tracer retention. ular techniques provided the basis to help explain model-specific Methods: Four weeks after orthotopic inoculation of human pan- tracer uptake patterns in xenotransplanted human tumor cell creatic carcinoma cells (PancTuI, Colo357, and BxPC3) into lines in mice as observed by PET. SCID mice, combined imaging was performed with a small- Key Words: pancreatic carcinoma; 18F-fluorodeoxyglucose; animal PET scanner and a 3-T MRI scanner using a dedicated 18F-fluorothymidine; 18F-fluorethylcholine; MRI; PET; SCID mouse coil. Tumor-to-liver uptake ratios (TLRs) of the tracers mice; orthotopic xenotransplantation model; gene array were compared with gene expression profiles of the tumor cell J Nucl Med 2008; 49:1362–1370 lines and both normal pancreatic tissue and pancreatic tumor tis- DOI: 10.2967/jnumed.107.050021 sue based on gene microarray analysis and quantitative poly- merase chain reaction. Results: 18F-FLT showed the highest tumor uptake, with a mean TLR of 2.3, allowing correct visualiza- tion of all 12 pancreatic tumors. 18F-FDG detected only 4 of 8 tu- mors and had low uptake in tumors, with a mean TLR of 1.1 in ancreatic ductal adenocarcinoma (PDAC) is often de- 18 P visible tumors. F-FEC did not show any tumor uptake. Gene ar- tected at an advanced tumor stage, which, among other ray analysis revealed that both hexokinase 1 as the rate-limiting enzyme for 18F-FDG trapping and pancreas-specific glucose reasons, contributes to its dismal prognosis. The only curative transporter 2 were significantly downregulated whereas thymi- option, radical surgical resection (Kausch-Whipple proce- dine kinase 1, responsible for 18F-FLT trapping, was significantly dure) combined with lymphadenectomy, can raise the 5-y- upregulated in the tumor cell lines, compared with normal pan- survival rates to 20%–30% (1,2). creatic duct cells and pancreatic tumor tissue. Relevant genes Suitable animal models that mimic the clinical situation involved in the uptake of 18F-FEC were predominantly unaffected as closely as possible are essential for developing and com- or downregulated in the tumor cell lines. Conclusion: In compar- paring new diagnostic and therapeutic strategies. Recently, ison to 18F-FDG and 18F-FEC, 18F-FLT was the PET tracer with we developed and described a clinically adapted orthotopic xenotransplantation model of pancreatic cancer that reflects the clinical situation in terms of local growth and metastasis Received Dec. 19, 2007; revision accepted Apr. 22, 2008. (3). This model allows systematic preclinical in vivo testing For correspondence or reprints contact: Winfried Brenner, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, of any new diagnostic and therapeutic option. Germany. For both early staging and precise treatment monitoring, E-mail: [email protected] *Contributed equally to this work. reliable diagnostic tools are mandatory. Abdominal or endo- COPYRIGHT ª 2008 by the Society of Nuclear Medicine, Inc. scopic ultrasonography with or without fine-needle aspiration, 1362 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 49 • No. 8 • August 2008 jnm050021-sn n 7/11/08 CT, MRI, and endoscopic retrograde cholangiopancreatog- MATERIALS AND METHODS raphy are the most frequently used diagnostic procedures Preparation of Radiopharmaceuticals for evaluation of patients in whom pancreatic cancer is 18F-FDG was synthesized in a commercial synthesis module clinically suspected (4,5). However, these methods have (Nuclear Interface) using a modification of the technique de- their limitations in distinguishing pancreatic cancer from scribed by Hamacher et al. (20). chronic mass-forming pancreatitis and in differentiating vi- 18F-FLT was synthesized using 3-N-Boc-59-O-dimethoxytrityl- able tumor from posttherapeutic changes during follow-up 39-O-nosyl-thymidine (ABX; Advanced Biochemical Compounds) (5,6). as a precursor for use in a synthesis module developed in-house. The 18 PET with 18F-FDG has been demonstrated to be useful in precursor reacted with the F fluoride ions in the presence of evaluating indeterminate pancreatic masses, staging pancre- Kryptofix 2.2.2 (Merck) phase transfer catalyst in acetonitrile at 130°C. After subsequent hydrolysis with 1 M hydrochloric acid, atic cancer, detecting metastatic disease, and differentiating 18F-FLTwas purified on a semipreparative Nucleodur Pyramid C18 viable tumor from posttherapeutic changes (7–9). However, high-performance liquid chromatography column (Macherey- although critical, the differentiation of pancreatic malig- Nagel). The column was eluted with a mobile phase of 7.5% ethanol nancy from focal pancreatitis, as well as tumor detection in in 0.015 M phosphate buffer (pH 5.5). The final product had a cases of coexisting pancreatitis, is still a challenge by means specific activity of 2–5 GBq/mmol, with a radiochemical purity of of 18F-FDG PET (10). more than 99%. Shields et al. first reported the potential utility of 3-deoxy- 18F-FEC was synthesized by a 2-step 1-pot method similar to that 3-18F-fluorothymidine (18F-FLT) for the noninvasive de- of Hara et al. (21). First, the dried 18F fluoride ions reacted with 1,2 tection of cell proliferation using PET (11). 18F-FLT is bis(tosyloxy)ethane (Fluorochem Ltd.) in the presence of Kryptofix transported through the cell membrane and trapped inside 2.2.2 phase transfer catalyst in acetonitrile at 80°C. After the the cell after phosphorylation by thymidine kinase 1 (TK1). reaction was completed, the acetonitrile was evaporated at 60°C with helium flow, yielding 2-18F-fluoroethyl tosylate. Subsequently, Although 18F-FLT is not incorporated into the DNA, it is still 0.5 mL of di-methyl-aminoethanol was added. The second reaction considered a surrogate marker of cellular proliferation be- took place at 100°C, resulting in 18F-FEC. The unreacted precursor cause TK1 activity is closely regulated by the cell cycle (12). was evaporated at 130°C. The dried residue was dissolved in 2 mL of 18 A close relationship between F-FLT tumor retention and water and passed through a cation exchange cartridge (Sep-Pak cell proliferation could be demonstrated, suggesting that 18F- Accell Plus CM; Waters Corp.). The cartridge was washed with 10 FLTis a promising marker for monitoring treatment response mL of ethanol and 10 mL of water subsequently, and 18F-FEC was (13,14). In contrast to 18F-FDG, 18F-FLT is not taken up by eluted with 5 mL of saline solution from the cartridge. After sterile inflammatory cells (15), potentially reducing the rate of filtration, the ready-to-use product had a radiochemical purity of false-positive findings both in pancreatitis and in inflamma- more than 99%. tory tissue after therapy. Another PET tracer that recently came into the focus of Laboratory Animals tumor imaging is 18F-fluorethylcholine (18F-FEC). PET Four-week-old female SCID beige mice weighing 14–19 g were with choline was first introduced for the evaluation of brain obtained from Harlan-Winkelmann. The mice were allowed to tumors (16) and more recently was examined for imaging become acclimatized for 10 d and were housed in a sterile environ- ment in which bedding, food, and water had been autoclaved prostate cancer and esophageal carcinoma (17,18). Choline (Scantainer). Animal experiments and animal care were in accor- is incorporated into cells through phosphoryl choline syn- dance with the guidelines of institutional committees and approved thesis and subsequent integration into membrane phospho- by local ethics and radiation safety authorities. lipids (19). Increased choline uptake therefore is expected in proliferating tumor cells.
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