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Development of Novel Approach to Diagnostic Imaging of Lung Cancer with 18F-Nifene PET/CT Using A/J Mice Treated with NNK

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Development of Novel Approach to Diagnostic Imaging of Lung Cancer with 18F-Nifene PET/CT Using A/J Mice Treated with NNK Journal of Cancer Research & Therapy NobleResearch Galitovskiy V et al., J Cancer Res Ther 2013, 1(4): 128-137 www.nobleresearch.org 0 http://dx.doi.org/10.14312/2052-4994.2013-2 Original Research Open Access Development of novel approach to diagnostic imaging of lung cancer with 18F-Nifene PET/CT using A/J mice treated with NNK Galitovskiy V1, Kuruvilla SA2, Sevriokov E2, Corches A2, Pan ML2, Kalantari-Dehaghi M1, Chernyavsky AI1, Mukherjee J2,3 and Grando SA1,3 1 2 3Department of Dermatology, University of California-Irvine, Irvine, CA 92697, USA Preclinical Imaging, Department of Radiological Sciences, University of California-Irvine, Irvine, CA 92697, USA Cancer Center and Research Institute, University of California-Irvine, Irvine, CA 92697, USA Abstract oncology. In this study, we utilized the tobacco nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung cancerDevelopment in A/J miceof novel as anmethods animal of model early fordiagnosis development of lung ofcancer a new is imaging one of the technique major tasks for early of contemporary diagnosis of clinicallung cancer. and experimental Lung cancer NNK treatment, followed by PET/CT scans with 18F-Nifene that binds to ofcells lungs in A/J were mice also overexpress obtained ex nicotinic vivo. CT acetylcholine revealed the receptors. presence ofLongitudinal lung nodules CT inscans 8-month were carriedNNK-treated out over mice, a period while ofcontrol 8 months mice after had no tumors. Imaging of live animals prior to necropsy allowed correlation4-made of results nicotinic of tumor receptors load via with PET/CT high affinity.and histopathological PET/CT scans 18F-Nifene was seen in the lungs of NNK-treated mice, whereas lungs of control mice showed only minor uptake of 18 18F-Nifene binding in lung in vivo and ex vivo demonstrated a findings. Significant amount of 4 nicotinic receptor subunits. For comparison,F-Nifene. we performed Quantitative PET/CT analysis studies of with the 18 extentF-FDG, and which amount is used of for the imaging diagnosis of lung cancer. The tumor/nontumor ratioshigher for tumor/nontumor 18F-FDG were lower ratio than due forto selective18F-Nifene. labeling Thus, we of havetumor developed nodules expressinga novel diagnostic abundant imaging approach to early diagnosis of lung cancer using 18F-Nifene PET/CT. This technique allows quantitative assessment of lung tumors in live mice, which is critical for establishing tumor size and location, and also has salient clinical implications. Keywords: 18F-Nifene; 18F-FDG; PET/CT imaging; nicotinic receptors; NNK; A/J mice; lung cancer Introduction Acetylcholine (ACh) is an auto/paracrine growth factor for lung cancer [4]. Recent studies have demonstrated Lung cancer is the leading cause of cancer death in industrialized countries with a high mortality rate and Corresponding authors: Grando SA, 134 Sprague Hall, University of 5-year survival rates of 15% [1]. Early detection of lung cancer is essential for early therapeutic interventions [email protected]; and Mukherjee J, B138 Medical California-Irvine, Irvine, CA 92697, USA. Tel.: 949-824-2713; Fax: 949- which can reduce mortality. Minimally invasive methods 824-2993, Email: [email protected] for early detection of lung cancer include computerized Sciences, University of California-Irvine, Irvine, CA 92697, USA. Tel.: Both senior authors contributed equally to this paper. tomography (CT) and positron emission tomography 949-824-2018; Fax: 949-824-2344, Email: (PET). A combination of PET/CT has been shown to have Received 3 March 2013 Revised 4 May 2013 Accepted 20 May 2013; Published a higher sensitivity of detection of the primary tumor and Citation: 29Galitovskiy May 2013 V, Kuruvilla SA, Sevriokov E, Corches A, Pan ML, metastases and also correlates with pathology [2]. The Kalantari-Dehaghi M, Chernyavsky AI, Mukherjee J, Grando SA (2013) 18 18F-FDG) PET/CT is being used Development of novel approach to diagnostic imaging of lung cancer for detection of the primary lung tumor and metastases. with 18F-Nifene PET/CT using A/J Mice treated with NNK. J Cancer Res Ther 1: 128-137. 0 However,F-fluorodeoxyglucose there is still a( substantial need for improving Copyright: ©2013doi:10.14312/2052-4994.2013-2 Galitovskiy V, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution than is currently possible [3]. This goal can be achieved by License, which permits unrestricted use, distribution and reproduction sensitivity and specificity of PET/CT lung cancer detection in any medium, provided the original author and source are credited. using more specific probes. Galitovskiy V et al., J Cancer Res Ther 2013, 1(4): 128-137 129 that the nicotinic class ACh receptors (nAChRs) act as We have developed and validated an imaging probe, central mediators in the cancer signaling pathways, and 18F-Nifene (Figure 1), which is suitable for non-invasive have unveiled previously unknown nicotinergic signaling visualization of 42 nAChRs using PET [30-32]. Normal networks in the lung (reviewed in [5-7]). nAChRs are classic lung distribution and kinetics of 18F-Nifene in mice was representatives of the superfamily of ligand-gated ion characterized by us in a previous work [33]. Binding and Ca2 and of 18F-Nifene in rat brain correlates very well with the [8]. The subunit genes encoding a pentameric known distribution of 4 125I- channel proteins mediating the influx of Na 1–10, 1– 2 receptors, as defined by efflux4, , of, and K with iodoepibatidine [30,18 34, 35] and confirmed in the studies thoughtprotein haveto be been limited identified to neurons and designated and skeletal muscles, evaluate utility of F-Nifene as an imaging probe in the 2-knockout mice (36). The goal of18 this study was to contemporary. Although research expression has convincingly of nAChRs demonstrated was originally early diagnosis of lung cancer. Since F-FDG PET/CT is routinely used for diagnosis of human lung tumors [2], comparative PET/CT studies were also carried out with nAChR subunits 2-10 and 2-4 in practically all cell 18 expression of different combinations of the "neuronal" F-FDG. diverse set of proteins, including the nAChRs themselves types [9]. Activation of nAChRs modulates expression of a As an animal model of lung cancer, we chose A/J mice treated with NNK. This model has been employed by us in [10-16], which can contribute to the carcinogenic action a carcinogen and appearance of multiple tumor nodules of tobacco constituents [10, 17-19]. The nAChR subtypes previous studies [37, 38]. The time between exposure to thein lung 3, epithelial4, 5, and cells 7 subunitsare well-characterized. that form nAChR In 1997,channels we tumors display a histological pattern characteristic modulatingfirst demonstrated Ca2 that human bronchial cells express ofin thealveolobronchial lungs is relatively adenomas short: 4 toand 5 monthsalveolobronchial [39]. The adenocarcinomas [40, 41] resembling the human lung metabolism [20]. These findings have adenocarcinoma that has increased in incidence in the been confirmed in other laboratories [21-23]. United States [42]. Mouse tumors originate from the same and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone cells—the type II alveolar epithelial cells and Clara cells. (NNK)Tobacco-specific (Figure 1),nitrosamines, are nicotine N'-nitrosonornicotine metabolites and powerful lung carcinogens that bind to nAChRs [24, 25]. The lung adenocarcinoma developing in A/J mice exposed to tobacco products is associated with overexpression of nAChRs and relies on nAChR18 signaling [10, 19]. Exposure to nicotine or NNK activates and upregulates Herein, we report the use of F-Nifene in the longitudinal respiratory nAChRs [10, 16, 19, 20, 26, 27]. Bronchial PET/CT studies of lung tumors in A/J mice treated with 4- cell transformation also alters the expression of nAChR subunit profiles [4, 23, 28]. The nAChR subtypes are targetNNK. Thesefor 18F tumors-Nifene. wereThe resultsfound todemonstrated overexpress thatthe our overexpressed in a variety of cancers, including lung sensitive methods of early diagnosis of lung cancer may newlymade nAChRsdeveloped providing 18F-Nifene the tumor- PET/CT selective method and specificallows cancer [6, 7, 29]. Hence, development of novel and more be based on visualizing nAChRs on cancer cells. However, quantitative assessment of lung tumors in live mice, which there have been no reports on in vivo visualization of lung is critical for establishing tumor size and location, and has cancer using the nAChR imaging probes. salient clinical implications. Materials and methods A/J mouse model of lung cancer from Jackson Laboratories (Bar Harbor, ME). Mice Female strain A/J mice, 6–8 weeks old, were purchased tobacco nitrosamines [43]. The animals were housed in a. Nicotine b. NNN of this strain develop lungad tumorslibitum accesswhen toexposed food and to water, and conventional bedding material. Mice were treatedpolypropylene in accordance boxes with to National Institutes of Health guidelines and as approved by the Institutional Animal Care and Use Committee of the University of California, Irvine. Mice were divided into three groups, 12 per group subcutaneous injection of 100 l in the upper back at a dose(Figure of 1002). Experimental mg/kg once a mice week were for fourtreated weeks. with NNK NNK was by c. NNK d. 18F-Nifene Figure 1 Chemical structures of 18F-Nifene and NNK. Structure of nicotine, weredissolved injected in DMSO with thein 10x same concentration solution without and dilutedNNK. The in its metabolites N’-nitrosonornicotine (NNN) and 4-(methylnitrosamino)- corn oil to final concentration. Treatment control mice 1-(3-pyridyl)-1-butanone (NNK), as well as 18F-Nifene. CT/PET control mice were also included because multiple Galitovskiy V et al., J Cancer Res Ther 2013, 1(4): 128-137 130 Figure 2 Study time-line. Time-line of CT and PET scans of A/J mice injected with NNK vs.
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