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Find video protocols related to scientific articles indexed in Pubmed.
A multifractal approach to space-filling recovery for PET quantification.
Med Phys
PUBLISHED: 11-06-2014
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A new image-based methodology is developed for estimating the apparent space-filling properties of an object of interest in PET imaging without need for a robust segmentation step and used to recover accurate estimates of total lesion activity (TLA).
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I??? inhibits apoptosis at the outer mitochondrial membrane independently of NF-?B retention.
EMBO J.
PUBLISHED: 11-02-2014
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I?B? resides in the cytosol where it retains the inducible transcription factor NF-?B. We show that I?B? also localises to the outer mitochondrial membrane (OMM) to inhibit apoptosis. This effect is especially pronounced in tumour cells with constitutively active NF-?B that accumulate high amounts of mitochondrial I?B? as a NF-?B target gene. 3T3 I?B?(-/-) cells also become protected from apoptosis when I?B? is specifically reconstituted at the OMM. Using various I?B? mutants, we demonstrate that apoptosis inhibition and NF-?B inhibition can be functionally and structurally separated. At mitochondria, I?B? stabilises the complex of VDAC1 and hexokinase II (HKII), thereby preventing Bax recruitment to VDAC1 and the release of cytochrome c for apoptosis induction. When I?B? is reduced in tumour cells with constitutively active NF-?B, they show an enhanced response to anticancer treatment in an in vivo xenograft tumour model. Our results reveal the unexpected activity of I?B? in guarding the integrity of the OMM against apoptosis induction and open possibilities for more specific interference in tumours with deregulated NF-?B.
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Positron emission tomographic imaging of CXCR4 in cancer: challenges and promises.
Mol Imaging
PUBLISHED: 10-25-2014
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AbstractMolecular imaging is an attractive platform for noninvasive detection and assessment of cancer. In recent years, the targeted imaging of the C-X-C chemokine receptor 4 (CXCR4), a chemokine receptor that has been associated with tumor metastasis, has become an area of intensive research. This review article focuses on positron emission tomography (PET) and aims to provide useful and critical insights into the application of PET to characterize CXCR4 expression, including the chemical, radiosynthetic, and biological requirements for PET radiotracers. This discussion is informed by a summary of the different approaches taken so far and a comparison of their clinical translation. Finally, our expert opinions as to potential future advances in the field are expressed.
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Clinical Translation of Molecular Imaging Agents Used in PET Studies of Cancer.
Adv. Cancer Res.
PUBLISHED: 10-08-2014
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Over recent years, there has been a rapid expansion in our knowledge of the factors that regulate tumor growth; this has resulted in the identification of new therapeutic targets and improvements in the long-term survival of cancer patients. New noninvasive biomarkers of drug targets and pathway modulation in vivo are needed to guide therapy selection and detect drug resistance early so that alternative, more effective treatments can be offered. The translation of new therapeutics into the clinic is disappointingly slow, expensive, and subject to high rates of attrition often occurring at late stages (phase 3) of development. In an attempt to mitigate these delays and failures, there has been resurgence in the development of new molecular imaging probes for studies with positron emission tomography (PET) to characterize tumor biology. In the assessment of therapeutic effects, PET allows imaging of entire tumor burden in a noninvasive repeatable manner. This chapter focuses on the clinical translation of PET imaging agents from bench to bedside. New probes are being used to study a diverse range of processes such as angiogenesis, apoptosis, fatty acid metabolism, and growth factor receptor expression. In the future, validation of these novel imaging probes could allow more innovative therapies to be adapted earlier in the clinic leading to improved patient outcomes.
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Alterations of Choline Phospholipid Metabolism in Endometrial Cancer Are Caused by Choline Kinase Alpha Overexpression and a Hyperactivated Deacylation Pathway.
Cancer Res.
PUBLISHED: 09-29-2014
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Metabolic rearrangements subsequent to malignant transformation are not well characterized in endometrial cancer. Identification of altered metabolites could facilitate imaging-guided diagnosis, treatment surveillance, and help to identify new therapeutic options. Here, we used high-resolution magic angle spinning magnetic resonance mass spectroscopy on endometrial cancer surgical specimens and normal endometrial tissue to investigate the key modulators that might explain metabolic changes, incorporating additional investigations using qRT-PCR, Western blotting, tissue microarrays (TMA), and uptake assays of [(3)H]-labeled choline. Lipid metabolism was severely dysregulated in endometrial cancer with various amino acids, inositols, nucleobases, and glutathione also altered. Among the most important lipid-related alterations were increased phosphocholine levels (increased 70% in endometrial cancer). Mechanistic investigations revealed that changes were not due to altered choline transporter expression, but rather due to increased expression of choline kinase ? (CHKA) and an activated deacylation pathway, as indicated by upregulated expression of the catabolic enzymes LYPLA1, LYPLA2, and GPCPD1. We confirmed the significance of CHKA overexpression on a TMA, including a large series of endometrial hyperplasia, atypical hyperplasia, and adenocarcinoma tissues, supporting a role for CHKA in malignant transformation. Finally, we documented several-fold increases in the uptake of [(3)H]choline in endometrial cancer cell lines compared with normal endometrial stromal cells. Our results validate deregulated choline biochemistry as an important source of noninvasive imaging biomarkers for endometrial cancer. Cancer Res; 74(23); 1-11. ©2014 AACR.
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Anti-nicastrin monoclonal antibodies elicit pleiotropic anti-tumour pharmacological effects in invasive breast cancer cells.
Breast Cancer Res. Treat.
PUBLISHED: 08-26-2014
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The goal of targeted cancer therapies is to specifically block oncogenic signalling, thus maximising efficacy, while reducing side-effects to patients. The gamma-secretase (GS) complex is an attractive therapeutic target in haematological malignancies and solid tumours with major pharmaceutical activity to identify optimal inhibitors. Within GS, nicastrin (NCSTN) offers an opportunity for therapeutic intervention using blocking monoclonal antibodies (mAbs). Here we explore the role of anti-nicastrin monoclonal antibodies, which we have developed as specific, multi-faceted inhibitors of proliferation and invasive traits of triple-negative breast cancer cells. We use 3D in vitro proliferation and invasion assays as well as an orthotopic and tail vail injection triple-negative breast cancer in vivo xenograft model systems. RNAScope assessed nicastrin in patient samples. Anti-NCSTN mAb clone-2H6 demonstrated a superior anti-tumour efficacy than clone-10C11 and the RO4929097 small molecule GS inhibitor, acting by inhibiting GS enzymatic activity and Notch signalling in vitro and in vivo. Confirming clinical relevance of nicastrin as a target, we report evidence of increased NCSTN mRNA levels by RNA in situ hybridization (RNAScope) in a large cohort of oestrogen receptor negative breast cancers, conferring independent prognostic significance for disease-free survival, in multivariate analysis. We demonstrate here that targeting NCSTN using specific mAbs may represent a novel mode of treatment for invasive triple-negative breast cancer, for which there are few targeted therapeutic options. Furthermore, we propose that measuring NCSTN in patient samples using RNAScope technology may serve as companion diagnostic for anti-NCSTN therapy in the clinic.
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A bioorthogonal (68)Ga-labelling strategy for rapid in vivo imaging.
Chem. Commun. (Camb.)
PUBLISHED: 07-12-2014
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Herein, we describe a fast and robust method for achieving (68)Ga-labelling of the EGFR-selective monoclonal antibody (mAb) Cetuximab using the bioorthogonal Inverse-electron-Demand Diels-Alder (IeDDA) reaction. The in vivo imaging of EGFR is demonstrated, as well as the translation of the method within a two-step pretargeting strategy.
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Preclinical evaluation of 3-18F-fluoro-2,2-dimethylpropionic acid as an imaging agent for tumor detection.
J. Nucl. Med.
PUBLISHED: 07-10-2014
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Deregulated cellular metabolism is a hallmark of many cancers. In addition to increased glycolytic flux, exploited for cancer imaging with (18)F-FDG, tumor cells display aberrant lipid metabolism. Pivalic acid is a short-chain, branched carboxylic acid used to increase oral bioavailability of prodrugs. After prodrug hydrolysis, pivalic acid undergoes intracellular metabolism via the fatty acid oxidation pathway. We have designed a new probe, 3-(18)F-fluoro-2,2-dimethylpropionic acid, also called (18)F-fluoro-pivalic acid ((18)F-FPIA), for the imaging of aberrant lipid metabolism and cancer detection.
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Exploring the potential of [11C]choline-PET/CT as a novel imaging biomarker for predicting early treatment response in prostate cancer.
Nucl Med Commun
PUBLISHED: 06-26-2014
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The aim of the study was to assess the effects of neoadjuvant androgen deprivation (NAD) and radical prostate radiotherapy with concurrent androgen deprivation (RT-CAD) on prostatic [C]choline kinetics and thus develop methodology for the use of [C]choline-PET/computed tomography (CT) as an early imaging biomarker.
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Comparison between diffusion-weighted MRI (DW-MRI) at 1.5 and 3 tesla: a phantom study.
J Magn Reson Imaging
PUBLISHED: 06-14-2014
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To compare DW-MRI between 1.5 and 3 Tesla (T) in terms of image quality, apparent diffusion coefficient (ADC), reproducibility, lesion-to-background contrast and signal-to-noise ratio (SNR), using a test object.
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CXCR4-targeted and MMP-responsive iron oxide nanoparticles for enhanced magnetic resonance imaging.
Angew. Chem. Int. Ed. Engl.
PUBLISHED: 05-23-2014
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MRI offers high spatial resolution with excellent tissue penetration but it has limited sensitivity and the commonly administered contrast agents lack specificity. In this study, two sets of iron oxide nanoparticles (IONPs) were synthesized that were designed to selectively undergo copper-free click conjugation upon sensing of matrix metalloproteinase (MMP) enzymes, thereby leading to a self-assembled superparamagnetic nanocluster network with T2 signal enhancement properties. For this purpose, IONPs with bioorthogonal azide and alkyne surfaces masked by polyethylene glycol (PEG) layers tethered to CXCR4-targeted peptide ligands were synthesized and characterized. The IONPs were tested in?vitro and T2 signal enhancements of around 160?% were measured when the IONPs were incubated with cells expressing MMP2/9 and CXCR4. Simultaneous systemic administration of the bioorthogonal IONPs in tumor-bearing mice demonstrated the signal-enhancing ability of these 'smart' self-assembling nanomaterials.
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Variability of Proliferation and Diffusion in Different Lung Cancer Models as Measured by 3'-Deoxy-3'-18F-Fluorothymidine PET and Diffusion-Weighted MR Imaging.
J. Nucl. Med.
PUBLISHED: 04-28-2014
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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'-(18)F-fluorothymidine ((18)F-FLT) PET and diffusion-weighted (DW) MR imaging in lung carcinoma xenografts.
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Frequency and significance of physiological versus pathological uptake of 68Ga-DOTATATE in the pancreas: validation with morphological imaging.
Nucl Med Commun
PUBLISHED: 04-02-2014
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The objective of this study was to assess the relevance of physiological (68)Ga-DOTATATE PET/CT findings in the pancreas guided by morphological imaging (MI) in comparison with pathological tumour uptake in patients with neuroendocrine tumours (NETs).
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A novel radiotracer to image glycogen metabolism in tumors by positron emission tomography.
Cancer Res.
PUBLISHED: 03-05-2014
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The high rate of glucose uptake to fuel the bioenergetic and anabolic demands of proliferating cancer cells is well recognized and is exploited with (18)F-2-fluoro-2-deoxy-d-glucose positron emission tomography ((18)F-FDG-PET) to image tumors clinically. In contrast, enhanced glucose storage as glycogen (glycogenesis) in cancer is less well understood and the availability of a noninvasive method to image glycogen in vivo could provide important biologic insights. Here, we demonstrate that (18)F-N-(methyl-(2-fluoroethyl)-1H-[1,2,3]triazole-4-yl)glucosamine ((18)F-NFTG) annotates glycogenesis in cancer cells and tumors in vivo, measured by PET. Specificity of glycogen labeling was demonstrated by isolating (18)F-NFTG-associated glycogen and with stable knockdown of glycogen synthase 1, which inhibited (18)F-NFTG uptake, whereas oncogene (Rab25) activation-associated glycogen synthesis led to increased uptake. We further show that the rate of glycogenesis is cell-cycle regulated, enhanced during the nonproliferative state of cancer cells. We demonstrate that glycogen levels, (18)F-NFTG, but not (18)F-FDG uptake, increase proportionally with cell density and G1-G0 arrest, with potential application in the assessment of activation of oncogenic pathways related to glycogenesis and the detection of posttreatment tumor quiescence.
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PET imaging with multimodal upconversion nanoparticles.
Dalton Trans
PUBLISHED: 02-18-2014
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A series of new upconversion nanoparticles have been functionalised with tumour-targeting molecules and metal chelates, prepared following standard peptidic and thiol chemistry. The targeting strategy has been delivered via the ?v?3 integrin, which is a heterodimeric cell surface receptor that is up-regulated in a variety of cancers, such as melanoma and breast cancer. The well-known DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) motif allows coordination to the radionuclide (68)Ga. Radiolabelling experiments were optimised under relatively mild conditions, and are rare amongst nanoparticulate materials. In vivo application of these probes in mouse tumour models revealed their potential as specific cancer contrast agents for PET imaging.
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Biodistribution and radiation dosimetry of deuterium-substituted 18F-fluoromethyl-[1, 2-2H4]choline in healthy volunteers.
J. Nucl. Med.
PUBLISHED: 02-05-2014
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(11)C-choline and (18)F-fluoromethylcholine ((18)F-FCH) have been used in patients to study tumor metabolic activity in vivo; however, both radiotracers are readily oxidized to respective betaine analogs, with metabolites detectable in plasma soon after injection of the radiotracer. A more metabolically stable FCH analog, (18)F-fluoromethyl-[1,2-(2)H4]choline ((18)F-D4-FCH), based on the deuterium isotope effect, has been developed. We report the safety, biodistribution, and internal radiation dosimetry profiles of (18)F-D4-FCH in 8 healthy human volunteers.
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Positron emission tomography imaging with 18F-labeled ZHER2:2891 affibody for detection of HER2 expression and pharmacodynamic response to HER2-modulating therapies.
Clin. Cancer Res.
PUBLISHED: 02-03-2014
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Expression of HER2 has profound implications on treatment strategies in various types of cancer. We investigated the specificity of radiolabeled HER2-targeting ZHER2:2891 Affibody, [(18)F]GE-226, for positron emission tomography (PET) imaging.
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Phosphorylation status of thymidine kinase 1 following antiproliferative drug treatment mediates 3'-deoxy-3'-[18F]-fluorothymidine cellular retention.
PLoS ONE
PUBLISHED: 01-01-2014
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3'-Deoxy-3'-[18F]-fluorothymidine ([18F]FLT) is being investigated as a Positron Emission Tomography (PET) proliferation biomarker. The mechanism of cellular [18F]FLT retention has been assigned primarily to alteration of the strict transcriptionally regulated S-phase expression of thymidine kinase 1 (TK1). This, however, does not explain how anticancer agents acting primarily through G2/M arrest affect [18F]FLT uptake. We investigated alternative mechanisms of [18F]FLT cellular retention involving post-translational modification of TK1 during mitosis.
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Preclinical assessment of carboplatin treatment efficacy in lung cancer by 18F-ICMT-11-positron emission tomography.
PLoS ONE
PUBLISHED: 01-01-2014
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Tumour response to therapy is assessed primarily in the clinic by monitoring reductions in tumour size. However, this approach lacks sensitivity since in many cases several weeks may elapse before there is evidence of tumour shrinkage. There is therefore a need to develop non-invasive imaging techniques for monitoring tumour treatment response in the clinic. Here, we assessed the pre-clinical utility of (18)F-ICMT-11 positron emission tomography--a method for detecting caspase 3/7 activation--in non-small cell lung cancer (NSCLC). (18)F-ICMT-11 uptake was compared to molecular biochemical measures of cell death in PC9 and A549 NSCLC cells following treatment with carboplatin in vitro and in vivo. Carboplatin-induced apoptosis in the ERCC1 low/mutant EGFR PC9 cells was characterised by time and dose-related increased caspase-3/7 activation, poly-ADP-ribose polymerase cleavage and Annexin V staining. 18F-ICMT-11 uptake was consequently increased up to 14-fold at 200 µM carboplatin compared to vehicle treated cells (P<0.01). In contrast, necrosis was the predominant death mechanism in ERCC1 high/wt EGFR A549 cells and no change in (18)F-ICMT-11 uptake was detected. In vivo, histological analysis of PC9 tumour xenografts indicated high pre-therapy necrosis. A 4.6-fold increase in cleaved caspase-3/7 was measured in non-necrotic regions of PC9 tumours at 48 h post carboplatin therapy. Average PET-derived tumour (18)F-ICMT-11 uptake was insensitive to changes in apoptosis in the presence of substantial pre-existing necrosis. PET-based voxel intensity sorting however, identified intra-tumoural regions of high (18)F-ICMT-11 uptake, enabling accurate assessment of apoptosis and therefore therapy response. In A549 tumours that lacked high pre-therapy necrosis, carboplatin induced growth inhibition that was only minimally associated with apoptosis and thus not detectable by (18)F-ICMT-11 PET.
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Radiolabeled RGD Tracer Kinetics Annotates Differential ?v? 3 Integrin Expression Linked to Cell Intrinsic and Vessel Expression.
Mol Imaging Biol
PUBLISHED: 09-12-2013
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The purpose of this paper is to study the association between RGD binding kinetics and ?v?3 integrin receptor density in the complex tumor milieu.
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Preclinical evaluation of a CXCR4-specific (68)Ga-labelled TN14003 derivative for cancer PET imaging.
Bioorg. Med. Chem.
PUBLISHED: 09-11-2013
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Molecular imaging is an ideal platform for non-invasive detection and assessment of cancer. In recent years, the targeted imaging of CXCR4, a chemokine receptor that has been associated with tumour metastasis, has become an area of intensive research. In our pursuit of a CXCR4-specific radiotracer, we designed and synthesised a novel derivative of the CXCR4 peptidic antagonist TN14003, CCIC16, which is amenable to radiolabelling by chelation with a range of PET and SPECT radiometals, such as (68)Ga, (64)Cu and (111)In as well as (18)F (Al(18)F). Potent in vitro binding affinity and inhibition of signalling-dependent cell migration by unlabelled CCIC16 were confirmed by a threefold uptake in CXCR4-over-expressing cells compared to their isogenic counterparts. Furthermore, in vivo experiments demonstrated the favourable pharmacokinetic properties of the (68)Ga-labelled tracer (68)Ga-CCIC16, along with its CXCR4-specific accumulation in tissues with desirable contrast (tumour-to-muscle ratio: 9.5). The specificity of our tracer was confirmed by blocking experiments. Taking into account the attractive intrinsic PET imaging properties of (68)Ga, the comprehensive preclinical evaluation presented here suggests that (68)Ga-CCIC16 is a promising PET tracer for the specific imaging of CXCR4-expressing tumours.
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Synthesis of a new fluorine-18 glycosylated click cyanoquinoline for the imaging of epidermal growth factor receptor.
J Labelled Comp Radiopharm
PUBLISHED: 08-29-2013
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This study reports the radiosynthesis of a new fluorine-18 glycosylated click cyanoquinoline [(18) F]5 for positron emission tomography imaging of epidermal growth factor receptor (EGFR). The tracer was obtained in 47.7?±?7.5% (n?=?3) decay-corrected radiochemical yield from 2-[(18) F]fluoro-2-deoxy-?-d-glucopyranosyl azide, and the overall nondecay-corrected radiochemical yield from aqueous fluoride was 8.6?±?2.3% (n?=?3). An in vitro preliminary cellular uptake study showed selectivity of the tracer for EGFR-positive A431 cell lines versus EGFR-negative MCF-7 cell lines. [(18) F]5 tracer uptake in A431 cells was significantly reduced by addition of the cold isotope analogue compound 5.
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18F-ICMT-11, a caspase-3-specific PET tracer for apoptosis: biodistribution and radiation dosimetry.
J. Nucl. Med.
PUBLISHED: 08-15-2013
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Effective anticancer therapy induces tumor cell death through apoptosis. Noninvasive monitoring of apoptosis during therapy may provide predictive outcome information and help tailor treatment. A caspase-3-specific imaging radiotracer, (18)F-(S)-1-((1-(2-fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-5-(2(2,4-difluorophenoxymethyl)-pyrrolidine-1-sulfonyl)isatin ((18)F-ICMT-11), has been developed for use in PET studies. We report the safety, biodistribution, and internal radiation dosimetry profiles of (18)F-ICMT-11 in 8 healthy human volunteers.
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Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer.
Breast Cancer Res.
PUBLISHED: 08-08-2013
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Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice.
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Bioorthogonal chemistry for pre-targeted molecular imaging--progress and prospects.
Org. Biomol. Chem.
PUBLISHED: 08-03-2013
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The aim of this perspective is to critically review the three most prominent bioorthogonal reactions that are used presently, on both a purely chemical level and in the context of biological systems. This includes the uses both for synthesis of therapeutic molecules, modification of large biomolecules or antibodies, and in particular, the exciting use in the field of pre-targeting, for both possible treatment and imaging technologies. We will compare the validity of each reaction when compared to others, and their usefulness in biological systems, as each methodology has clear advantages over the others in differing environments.
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Heterogeneity in lung (18)FDG uptake in pulmonary arterial hypertension: potential of dynamic (18)FDG positron emission tomography with kinetic analysis as a bridging biomarker for pulmonary vascular remodeling targeted treatments.
Circulation
PUBLISHED: 07-30-2013
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Pulmonary arterial hypertension (PAH) is a disease of progressive vascular remodeling, characterized by dysregulated growth of pulmonary vascular cells and inflammation. A prevailing view is that abnormal cellular metabolism, notably aerobic glycolysis that increases glucose demand, underlies the pathogenesis of PAH. Increased lung glucose uptake has been reported in animal models. Few data exist from patients with PAH.
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Magnetic nanoparticles as contrast agents in the diagnosis and treatment of cancer.
Chem Soc Rev
PUBLISHED: 06-21-2013
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Magnetic nanoparticles represent one of the most advanced developments in the application of nanotechnology to human health. To date, their clinical application has been restricted to the diagnosis of hepatic lesions and lymph node metastasis but functionalization of these materials with biomolecules as targeting motifs, and the inclusion of therapeutic drugs in their composition, is certain to make a substantial impact within biomedicine. One of the diseases that could benefit from these advances is cancer, as early diagnosis and effective treatment are crucial for a patients survival and quality of life. This review will examine the recent uses of magnetic particles in cancer diagnosis and treatment.
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Bioorthogonal chemistry for (68) Ga radiolabelling of DOTA-containing compounds.
J Labelled Comp Radiopharm
PUBLISHED: 06-04-2013
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Copper-catalysed click chemistry is a highly utilised technique for radiolabelling small molecules and peptides for imaging applications. The usefulness of these reactions falls short, however, when metal catalysis is not a practically viable route; such as when using metal chelates as radioligands. Here, we describe a method for carrying out click-type radiochemistry in the presence of DOTA chelates, by combining (68) Ga radiolabelling techniques with well-established bioorthogonal reactions, which do not rely upon metal catalysis.
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Temporal and spatial evolution of therapy-induced tumor apoptosis detected by caspase-3-selective molecular imaging.
Clin. Cancer Res.
PUBLISHED: 05-31-2013
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Induction of apoptosis in tumors is considered a desired goal of anticancer therapy. We investigated whether the dynamic temporal and spatial evolution of apoptosis in response to cytotoxic and mechanism-based therapeutics could be detected noninvasively by the caspase-3 radiotracer [(18)F]ICMT-11 and positron emission tomography (PET).
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A phantom for diffusion-weighted MRI (DW-MRI).
J Magn Reson Imaging
PUBLISHED: 04-10-2013
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To develop tissue-equivalent diffusivity materials and build a spherical diffusion phantom which mimics the conditions typically found in biological tissues. Also, to assess the reproducibility of ADC measurements from a whole-body diffusion protocol.
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Introduction to the analysis of PET data in oncology.
J Pharmacokinet Pharmacodyn
PUBLISHED: 02-13-2013
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Several reviews on specific topics related to positron emission tomography (PET) ranging in complexity from introductory to highly technical have already been published. This introduction to the analysis of PET data was written as a simple guide of the different phases of analysis of a given PET dataset, from acquisition to preprocessing, to the final data analysis. Although sometimes issues specific to PET in neuroimaging will be mentioned for comparison, most of the examples and applications provided will refer to oncology. Due to the limitations of space we couldnt address each issue comprehensively but, rather, we provided a general overview of each topic together with the references that the interested reader should consult. We will assume a familiarity with the basic principles of PET imaging.
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Visualising androgen receptor activity in male and female mice.
PLoS ONE
PUBLISHED: 01-01-2013
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Androgens, required for normal development and fertility of males and females, have vital roles in the reproductive tract, brain, cardiovascular system, smooth muscle and bone. Androgens function via the androgen receptor (AR), a ligand-dependent transcription factor. To assay and localise AR activity in vivo we generated the transgenic "ARE-Luc" mouse, expressing a luciferase reporter gene under the control of activated endogenous AR. In vivo imaging of androgen-mediated luciferase activity revealed several strongly expressing tissues in the male mouse as expected and also in certain female tissues. In males the testes, prostate, seminal vesicles and bone marrow all showed high AR activity. In females, strong activity was seen in the ovaries, uterus, omentum tissue and mammary glands. In both sexes AR expression and activity was also found in salivary glands, the eye (and associated glands), adipose tissue, spleen and, notably, regions of the brain. Luciferase protein expression was found in the same cell layers as androgen receptor expression. Additionally, mouse AR expression and activity correlated well with AR expression in human tissues. The anti-androgen bicalutamide reduced luciferase signal in all tissues. Our model demonstrates that androgens can act in these tissues directly via AR, rather than exclusively via androgen aromatisation to estrogens and activation of the estrogen receptor. Additionally, it visually demonstrates the fundamental importance of AR signalling outside the normal role in the reproductive organs. This model represents an important tool for physiological and developmental analysis of androgen signalling, and for characterization of known and novel androgenic or antiandrogenic compounds.
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Design, synthesis and in vitro characterization of fluorescent and paramagnetic CXCR4-targeted imaging agents.
Am J Nucl Med Mol Imaging
PUBLISHED: 01-01-2013
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The G-protein coupled C-X-C chemokine receptor type 4 (CXCR4) is highly overexpressed in a range of cancers and is therefore an excellent biomarker for cancer imaging. To this end targeted iron oxide nanoparticles were developed and utilised for in vitro imaging of MDA-MB-231 breast cancer cells overexpressing the CXCR4 receptor. Nanoparticles comprising an iron oxide core, encapsulated in a stabilising epichlorohydrin crossed-linked dextran polymer, were conjugated to a cyclopentapeptide with affinity to the CXCR4 receptor. The particles were characterized for their size, surface charge and r2 relaxivity at 4.7 T. MR imaging of the CXCR4 receptor with targeted iron oxide nanoparticles revealed an approximately 3-fold increase in T2 signal enhancement of MDA-MB-231 cells compared to non-targeted controls. Prussian blue staining of labeled MDA-MB-231 cells revealed darker and more intense staining of the cellular membrane. This study demonstrates the potential of targeted iron oxide nanoparticles for the imaging of the CXCR4 receptor by magnetic resonance imaging (MRI).
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Copper-free click--a promising tool for pre-targeted PET imaging.
Chem. Commun. (Camb.)
PUBLISHED: 12-07-2011
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The copper-free click (CFC) reaction has been evaluated for its potential application to in vivo pre-targeting for PET imaging. A promising biodistribution profile is demonstrated when employing [(18)F]2-fluoroethylazide ([(18)F]1) and optimisation of the CFC reaction with a series of cyclooctynes shows that reactions proceed efficiently with tantalizing opportunities for application-specific tuning.
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[(18)F]FLT: an imaging biomarker of tumour proliferation for assessment of tumour response to treatment.
Eur. J. Cancer
PUBLISHED: 11-22-2011
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The paradigm of drug development is shifting towards early use of imaging biomarkers as surrogate end-points in clinical trials. Quantitative Imaging in Cancer: Connecting Cellular Processes (QuIC-ConCePT) is an initiative to qualify complementary imaging biomarkers (IB) of proliferation, cell death and tumour heterogeneity as possible tools in early phase clinical trials to help pharmaceutical developers in go, no-go decisions early in the process of drug development. One of the IBs is [(18)F]3-deoxy-3-fluorothymidine with Positron Emission Tomography (FLT-PET). We review results of recent clinical trials using FLT-PET for monitoring tumour response to drug treatment and discuss the potential and the possible pitfalls of using this IB as a surrogate end-point in early phase clinical trials for assessing tumour response to drug treatment. From first human trial results it seems that the degree of FLT accumulation in tumours is governed not only by the tumour proliferation rate but also by other factors. Nevertheless FLT-PET could potentially be used as a negative predictor of tumour response to chemotherapy, and hence evaluation of this IB is granted in multi-centre clinical trials.
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[18F]-3Deoxy-3-fluorothymidine positron emission tomography and breast cancer response to docetaxel.
Clin. Cancer Res.
PUBLISHED: 10-25-2011
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To establish biomarkers indicating clinical response to taxanes, we determined whether early changes in [(18)F]-3deoxy-3-fluorothymidine positron emission tomography (FLT-PET) can predict benefit from docetaxel therapy in breast cancer.
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Improved radiosynthesis of the apoptosis marker 18F-ICMT11 including biological evaluation.
Bioorg. Med. Chem. Lett.
PUBLISHED: 08-25-2011
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We improved the specific radioactivity of the apoptosis imaging isatin derivative (18)F-ICMT11. We then evaluated (18)F-ICMT11 in EL4 tumor-bearing mice 24h after treatment with etoposide/cyclophosphamide combination therapy. Dynamic PET imaging demonstrated increased uptake in the drug-treated (0.115±0.011 SUV) compared to the vehicle-treated EL4 tumors (0.083±0.008 SUV). This effect correlated to the observed increases in apoptotic index.
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Biological basis of [¹¹C]choline-positron emission tomography in patients with breast cancer: comparison with [¹?F]fluorothymidine positron emission tomography.
Nucl Med Commun
PUBLISHED: 08-25-2011
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The biological significance of [¹¹C]choline (CHO) uptake in human tumours is unclear and probably linked to choline kinase-? (CHK?) expression and cell proliferation. We directly compared CHO with [¹?F]fluorothymidine (FLT), an imaging biomarker of proliferation, by positron emission tomography (PET) in patients with breast cancer to investigate whether cell proliferation is an important determinant of CHO uptake. Furthermore, we evaluated CHK? and the Ki67-labelling index (LIKi67) in tumour biopsies.
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Targeting somatostatin receptors: preclinical evaluation of novel 18F-fluoroethyltriazole-Tyr3-octreotate analogs for PET.
J. Nucl. Med.
PUBLISHED: 08-18-2011
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The incidence and prevalence of gastroenteropancreatic neuroendocrine tumors has been increasing over the past 3 decades. Because of high densities of somatostatin receptors (sstr)--mainly sstr-2--on the cell surface of these tumors, (111)In-diethylenetriaminepentaacetic acid-octreotide scintigraphy has become an important part of clinical management. (18)F-radiolabeled analogs with suitable pharmacokinetics would permit PET with more rapid clinical protocols.
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Development of radiotracers for oncology--the interface with pharmacology.
Br. J. Pharmacol.
PUBLISHED: 07-13-2011
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There is an increasing role for positron emission tomography (PET) in oncology, particularly as a component of early phase clinical trials. As a non-invasive functional imaging modality, PET can be used to assess both pharmacokinetics and pharmacodynamics of novel therapeutics by utilizing radiolabelled compounds. These studies can provide crucial information early in the drug development process that may influence the further development of novel therapeutics. PET imaging probes can also be used as early biomarkers of clinical response and to predict clinical outcome prior to the administration of therapeutic agents. We discuss the role of PET imaging particularly as applied to phase 0 studies and discuss the regulations involved in the development and synthesis of novel radioligands. The review also discusses currently available tracers and their role in the assessment of pharmacokinetics and pharmacodynamics as applied to oncology.
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Adaptation to HIF-1 deficiency by upregulation of the AMP/ATP ratio and phosphofructokinase activation in hepatomas.
BMC Cancer
PUBLISHED: 05-25-2011
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HIF-1 deficiency has marked effects on tumour glycolysis and growth. We therefore investigated the consequences of HIF-1 deficiency in mice, using the well established Hepa-1 wild-type (WT) and HIF-1?-deficient (c4) model. These mechanisms could be clinically relevant, since HIF-1 is now a therapeutic target.
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Quantification of receptor-ligand binding with [¹?F]fluciclatide in metastatic breast cancer patients.
Eur. J. Nucl. Med. Mol. Imaging
PUBLISHED: 04-28-2011
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The purpose of the study was to estimate the receptor-ligand binding of an arginine-glycine-aspartic acid (RGD) peptide in somatic tumours. To this aim, we employed dynamic positron emission tomography (PET) data obtained from breast cancer patients with metastases, studied with the ?(v)?(3/5) integrin receptor radioligand [(18)F]fluciclatide.
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Glucose metabolism measured by [¹?F]fluorodeoxyglucose positron emission tomography is independent of PTEN/AKT status in human colon carcinoma cells.
Transl Oncol
PUBLISHED: 02-11-2011
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The phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most altered in cancer, leading to a range of cellular responses including enhanced proliferation, survival, and metabolism, and is thus an attractive target for anticancer drug development. Stimulation of the PI3K pathway can be initiated by alterations at different levels of the signaling cascade including growth factor receptor activation, as well as mutations in PIK3CA, PTEN, and AKT genes frequently found in a broad range of cancers. Given its role in glucose metabolism, we investigated the utility of [(18)F]fluorodeoxyglucose positron emission tomography ([(18)F]FDG PET) as a pharmacodynamic biomarker of PI3K pathway-induced glucose metabolism. PTEN deletion in human colon carcinoma cells led to constitutive AKT activation but did not confer a phenotype of increased cell proliferation or glucose metabolism advantage in vivo relative to isogenic tumors derived from cells with a wild-type allele. This was not due to the activation context, that is, phosphatase activity, per se because PIK3CA activation in xenografts derived from the same lineage failed to increase glucose metabolism. Acute inhibition of PI3K activity by LY294002, and hence decreased activated AKT expression, led to a significant reduction in tumor [(18)F]FDG uptake that could be explained at least in part by decreased membrane glucose transporter 1 expression. The pharmacodynamic effect was again independent of PTEN status. In conclusion, [(18)F]FDG PET is a promising pharmacodynamic biomarker of PI3K pathway inhibition; however, its utility to detect glucose metabolism is not directly linked to the magnitude of activated AKT protein expression.
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Synthesis and in vitro evaluation of [18F]fluoroethyl triazole labelled [Tyr3]octreotate analogues using click chemistry.
Bioorg. Med. Chem. Lett.
PUBLISHED: 01-07-2011
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A novel class of alkyne linked [Tyr(3)]octreotate analogues have been labelled by a copper catalysed azide-alkyne cycloaddition reaction (CuAAC) to form a 1,4-substituted triazole using the reagent [(18)F]2-fluoroethyl azide. An unexpected variability in reactivity during the CuAAC reaction was observed for each alkyne analogue which has been investigated. Two lead alkyne linked [Tyr(3)]octreotate analogues, G-TOCA (3a) and ?AG-TOCA (5a) have been identified to be highly reactive in the click reaction showing complete conversion to the [(18)F]2-fluoroethyl triazole linked [Tyr(3)]octreotate analogues FET-G-TOCA (3b) and FET-?AG-TOCA (5b) under mild conditions and with short synthesis times (5 min at 20 °C). As well as ease of synthesis, in vitro binding to the pancreatic tumour AR42J cells showed that both FET-G-TOCA and FET-?AG-TOCA have high affinity for the somatostatin receptor with IC(50) of 4.0±1.4, and 1.6±0.2 nM, respectively.
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A novel pyrazolo[1,5-a]pyrimidine is a potent inhibitor of cyclin-dependent protein kinases 1, 2, and 9, which demonstrates antitumor effects in human tumor xenografts following oral administration.
J. Med. Chem.
PUBLISHED: 11-16-2010
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Cyclin-dependent protein kinases (CDKs) are central to the appropriate regulation of cell proliferation, apoptosis, and gene expression. Abnormalities in CDK activity and regulation are common features of cancer, making CDK family members attractive targets for the development of anticancer drugs. Here, we report the identification of a pyrazolo[1,5-a]pyrimidine derived compound, 4k (BS-194), as a selective and potent CDK inhibitor, which inhibits CDK2, CDK1, CDK5, CDK7, and CDK9 (IC??= 3, 30, 30, 250, and 90 nmol/L, respectively). Cell-based studies showed inhibition of the phosphorylation of CDK substrates, Rb and the RNA polymerase II C-terminal domain, down-regulation of cyclins A, E, and D1, and cell cycle block in the S and G?/M phases. Consistent with these findings, 4k demonstrated potent antiproliferative activity in 60 cancer cell lines tested (mean GI??= 280 nmol/L). Pharmacokinetic studies showed that 4k is orally bioavailable, with an elimination half-life of 178 min following oral dosing in mice. When administered at a concentration of 25 mg/kg orally, 4k inhibited human tumor xenografts and suppressed CDK substrate phosphorylation. These findings identify 4k as a novel, potent CDK selective inhibitor with potential for oral delivery in cancer patients.
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Imaging the life and death of tumors in living subjects: Preclinical PET imaging of proliferation and apoptosis.
Integr Biol (Camb)
PUBLISHED: 08-25-2010
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Cancer is characterized by deregulation of cell proliferation and altered cell death apoptosis, which constitutes, in almost all instances, the minimal common platform upon which all neoplastic evolution occurs. The most implicit and clinically attractive anticancer strategies, therefore, consist of eliminating tumor cells by preventing their expansion and ultimately inducing cell death apoptosis. In this context, the non-invasive molecular assessment of tumor cell proliferation and apoptosis status using PET imaging constitutes a major strategy in preclinical studies to assess the efficacy of new anticancer therapeutics using small animal PET imaging, and in clinical settings for the monitoring of treatment responses in patients. For this purpose, a variety of PET tracers targeting specific molecular entities allowing the non-invasive measurement of biological processes, including cell proliferation and apoptosis, are under development for use in preclinical studies and clinical trials to non-invasively image in vivo the lifeline of tumors.
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Reproducibility of 18F-FDG and 3-deoxy-3-18F-fluorothymidine PET tumor volume measurements.
J. Nucl. Med.
PUBLISHED: 08-18-2010
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The objective of this study was to establish the repeatability and reproducibility limits of several volume-related PET image-derived indices-namely tumor volume (TV), mean standardized uptake value, total glycolytic volume (TGV), and total proliferative volume (TPV)-relative to those of maximum standardized uptake value (SUV(max)), commonly used in clinical practice.
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Reproducibility of [11C]choline-positron emission tomography and effect of trastuzumab.
Clin. Cancer Res.
PUBLISHED: 08-03-2010
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This study sought to evaluate the reproducibility of [(11)C]choline-positron emission tomography and the effect of trastuzumab in breast cancer.
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Radiosynthesis and pre-clinical evaluation of [(18)F]fluoro-[1,2-(2)H(4)]choline.
Nucl. Med. Biol.
PUBLISHED: 06-14-2010
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Choline radiotracers are widely used for clinical PET diagnosis in oncology. [(11)C]Choline finds particular utility in the imaging of brain and prostate tumor metabolic status, where 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) shows high background uptake. More recently we have extended the clinical utility of [(11)C]choline to breast cancer where radiotracer uptake correlates with tumor aggressiveness (grade). In the present study, a new choline analog, [(18)F]fluoro-[1,2-(2)H(4)]choline, was synthesized and evaluated as a potential PET imaging probe.
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Development of a new epidermal growth factor receptor positron emission tomography imaging agent based on the 3-cyanoquinoline core: synthesis and biological evaluation.
Bioorg. Med. Chem.
PUBLISHED: 02-26-2010
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The epidermal growth factor receptor (EGFR/c-ErbB1/HER1) is overexpressed in many cancers including breast, ovarian, endometrial, and non-small cell lung cancer. An EGFR specific imaging agent could facilitate clinical evaluation of primary tumors and/or metastases. To achieve this goal we designed and synthesized a small array of fluorine containing compounds based on a 3-cyanoquinoline core. A lead compound, 16, incorporating 2-fluoroethyl-1,2,3-triazole was selected for evaluation as a radioligand based on its high affinity for EGFR kinase (IC50=1.81+/-0.18 nM), good cellular potency (IC50=21.97+/-9.06 nM), low lipophilicity and good metabolic stability. Click labeling afforded [18F]16 in 37.0+/-3.6% decay corrected radiochemical yield based on azide [18F]14 and 7% end of synthesis (EOS) yield from aqueous fluoride. Compound [18F]16 was obtained with >99% radiochemical purity in a total synthesis time of 3 h. The compound showed good stability in vivo and a fourfold higher uptake in high EGFR expressing A431 tumor xenografts compared to low EGFR expressing HCT116 tumor xenografts. Furthermore, the radiotracer could be visualized in A431 tumor bearing mice by small animal PET imaging. Compound [18F]16 therefore constitutes a promising radiotracer for further evaluation for imaging of EGFR status.
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Kinetic filtering of [(18)F]Fluorothymidine in positron emission tomography studies.
Phys Med Biol
PUBLISHED: 01-13-2010
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[(18)F]Fluorothymidine (FLT) is a cell proliferation marker that undergoes predominantly hepatic metabolism and therefore shows a high level of accumulation in the liver, as well as in rapidly proliferating tumours. Furthermore, the tracers uptake is substantial in other organs including the heart. We present a nonlinear kinetic filtering technique which enhances the visualization of tumours imaged with FLT positron emission tomography (FLT-PET). A classification algorithm to isolate cancerous tissue from healthy organs was developed and validated using 29 scan data from patients with locally advanced or metastatic breast cancer. A large reduction in signal from the liver and heart of 80% was observed following application of the kinetic filter, whilst the majority of signal from both primary tumours and metastases was retained. A scan acquisition time of 60 min has been shown to be sufficient to obtain the necessary kinetic data. The algorithm extends utility of FLT-PET imaging in oncology research.
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The fibroblast growth factor receptor inhibitor PD173074 blocks small cell lung cancer growth in vitro and in vivo.
Cancer Res.
PUBLISHED: 11-10-2009
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Lung cancer is the commonest cancer killer. Small cell lung cancer (SCLC) is initially chemosensitive, but rapidly relapses in a chemoresistant form with an overall survival of <5%. Consequently, novel therapies are urgently required and will likely arise from an improved understanding of the disease biology. Our previous work showed that fibroblast growth factor-2 induces proliferation and chemoresistance in SCLC cells. Here, we show that the selective fibroblast growth factor receptor (FGFR) inhibitor PD173074 blocks H-510 and H-69 SCLC proliferation and clonogenic growth in a dose-dependent fashion and prevents FGF-2-induced chemoresistance. These effects correlate with the inhibition of both FGFR1 and FGFR2 transphosphorylation. We then determined the efficacy of daily oral administration of PD173074 for 28 days in two human SCLC models. In the H-510 xenograft, tumor growth was impaired similar to that seen with single-agent cisplatin administration, increasing median survival compared with control sham-treated animals. Crucially, the effect of cisplatin was significantly potentiated by coadministration of PD173074. More dramatically, in H-69 xenografts, PD173074 induced complete responses lasting >6 months in 50% of mice. These effects were not a consequence of disrupted tumor vasculature but instead correlated with increased apoptosis (caspase 3 and cytokeratin 18 cleavage) in excised tumors. Moreover, in vivo imaging with 3-deoxy-3-[(18)F]fluorothymidine-positron emission tomography ([(18)F]FLT-PET) showed decreased intratumoral proliferation in live animals treated with the compound at 7 to 14 days. Our results suggest that clinical trials of FGFR inhibitors should be undertaken in patients with SCLC and that [(18)F]FLT-PET imaging could provide early in vivo evidence of response.
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Altered tissue 3-deoxy-3-[18F]fluorothymidine pharmacokinetics in human breast cancer following capecitabine treatment detected by positron emission tomography.
Clin. Cancer Res.
PUBLISHED: 10-27-2009
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We showed in preclinical models that thymidylate synthase (TS) inhibition leads to redistribution of the nucleoside transporter, ENT1, to the cell membrane and hence increases tissue uptake of [(18)F]fluorothymidine (FLT). In this study, we assessed for the first time the altered pharmacokinetics of FLT in patients following administration of capecitabine, a drug whose mode of action has been reported to include TS inhibition.
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[18F]fluoromethyl-[1,2-2H4]-choline: a novel radiotracer for imaging choline metabolism in tumors by positron emission tomography.
Cancer Res.
PUBLISHED: 09-22-2009
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Current radiotracers for positron emission tomography imaging of choline metabolism have poor systemic metabolic stability in vivo. We describe a novel radiotracer, [(18)F]fluoromethyl-[1,2-(2)H(4)]-choline (D4-FCH), that employs deuterium isotope effect to improve metabolic stability. D4-FCH proved more resistant to oxidation than its nondeuterated analogue, [(18)F]fluoromethylcholine, in plasma, kidneys, liver, and tumor, while retaining phosphorylation potential. Tumor radiotracer levels, a determinant of sensitivity in imaging studies, were improved by deuterium substitution; tumor uptake values expressed as percent injected dose per voxel at 60 min were 7.43 +/- 0.47 and 5.50 +/- 0.49 for D4-FCH and [(18)F]fluoromethylcholine, respectively (P = 0.04). D4-FCH was also found to be a useful response biomarker. Treatment with the mitogenic extracellular kinase inhibitor PD0325901 resulted in a reduction in tumor radiotracer uptake that occurred in parallel with reductions in choline kinase A expression. In conclusion, D4-FCH is a very promising metabolically stable radiotracer for imaging choline metabolism in tumors.
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Positron emission tomography imaging of drug-induced tumor apoptosis with a caspase-3/7 specific [18F]-labeled isatin sulfonamide.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 09-03-2009
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Of the molecular biochemical alterations that occur during apoptosis, activation of caspases, notably caspase-3, is probably the most attractive for developing specific in vivo molecular imaging probes. We recently designed a library of isatin-5 sulfonamides and selected [18F]ICMT-11 for further evaluation on the basis of subnanomolar affinity for activated capsase-3, high metabolic stability, and facile radiolabeling. In this present study, we have demonstrated that [18F]ICMT-11 binds to a range of drug-induced apoptotic cancer cells in vitro and to 38C13 murine lymphoma xenografts in vivo by up to 2-fold at 24 h posttreatment compared to vehicle treatment. We further demonstrated that the increased signal intensity in tumors after drug treatment, detected by whole body in vivo microPET imaging, was associated with increased apoptosis. In summary, we have characterized [18F]ICMT-11 as a caspase-3/7 specific PET imaging radiotracer for the assessment of tumor apoptosis that could find utility in anticancer drug development and the monitoring of early responses to therapy.
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[11C]choline positron emission tomography in estrogen receptor-positive breast cancer.
Clin. Cancer Res.
PUBLISHED: 08-25-2009
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Novel radiotracers could potentially allow the identification of clinically aggressive tumor phenotypes. As choline metabolism increases during malignant transformation and progression of human mammary epithelial cells, we examined the ability of [(11)C]choline (CHO) positron emission tomography imaging to detect clinically aggressive phenotype in patients with estrogen receptor (ER)-positive breast cancer in vivo.
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The development of a selective cyclin-dependent kinase inhibitor that shows antitumor activity.
Cancer Res.
PUBLISHED: 07-28-2009
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Normal progression through the cell cycle requires the sequential action of cyclin-dependent kinases CDK1, CDK2, CDK4, and CDK6. Direct or indirect deregulation of CDK activity is a feature of almost all cancers and has led to the development of CDK inhibitors as anticancer agents. The CDK-activating kinase (CAK) plays a critical role in regulating cell cycle by mediating the activating phosphorylation of CDK1, CDK2, CDK4, and CDK6. As such, CDK7, which also regulates transcription as part of the TFIIH basal transcription factor, is an attractive target for the development of anticancer drugs. Computer modeling of the CDK7 structure was used to design potential potent CDK7 inhibitors. Here, we show that a pyrazolo[1,5-a]pyrimidine-derived compound, BS-181, inhibited CAK activity with an IC(50) of 21 nmol/L. Testing of other CDKs as well as another 69 kinases showed that BS-181 only inhibited CDK2 at concentrations lower than 1 micromol/L, with CDK2 being inhibited 35-fold less potently (IC(50) 880 nmol/L) than CDK7. In MCF-7 cells, BS-181 inhibited the phosphorylation of CDK7 substrates, promoted cell cycle arrest and apoptosis to inhibit the growth of cancer cell lines, and showed antitumor effects in vivo. The drug was stable in vivo with a plasma elimination half-life in mice of 405 minutes after i.p. administration of 10 mg/kg. The same dose of drug inhibited the growth of MCF-7 human xenografts in nude mice. BS-181 therefore provides the first example of a potent and selective CDK7 inhibitor with potential as an anticancer agent.
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Translational imaging of apoptosis.
Anticancer Agents Med Chem
PUBLISHED: 05-09-2009
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Deregulated apoptosis is involved in several diseases including myocardial infarction, ischemia and neurodegenerative disorders, which are characterized by excessive apoptosis. In contrast, resistance to apoptosis is defined as one of the hallmarks of cancer. It therefore follows that strategies that enable the quantitative detection of apoptosis modulation in vivo would be of enormous benefit in the clinic for diagnosis and patient management (evaluation of response to treatment). In addition, such strategies could be used to evaluate the efficacy of novel therapeutics along their development process. During the development of novel therapeutics it would be necessary to evaluate drug efficacy in vitro and then in experimental animal models and, ultimately, in clinical trials. Currently there is no one single probe that is suitable for imaging apoptosis at every stage of evaluation, necessitating a switch between probe types during the development process. This has key implications for the quality and reproducibility of the data obtained. The present review summarizes the development of new apoptosis detecting probes that have the potential for bridging different stages of the evaluation process such that accurate, translational apoptosis imaging data are obtained.
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Monitoring predominantly cytostatic treatment response with 18F-FDG PET.
J. Nucl. Med.
PUBLISHED: 05-01-2009
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(18)F-FDG PET and, more recently, PET/CT have been established as response biomarkers for monitoring cytotoxic or cytoreductive cancer therapies. With the advent of targeted cancer therapies, which are predominantly cytostatic, (18)F-FDG PET is increasingly being used to monitor the therapeutic response to these agents as well. The impressive outcome of (18)F-FDG PET studies in patients with gastrointestinal stromal tumors treated with imatinib mesylate brought to the forefront the use of this biomarker for assessing the response to targeted therapies. The use of (18)F-FDG PET for this purpose has practical challenges, including quantitative analysis and timing of scans. This review provides a summary of clinical studies of targeted therapies done to date with (18)F-FDG PET and provides guidance on practical issues to ensure the optimal interpretation of imaging data in drug development and for patient care.
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An in vivo multimodal imaging study using MRI and PET of stem cell transplantation after myocardial infarction in rats.
Mol Imaging Biol
PUBLISHED: 03-19-2009
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The purpose of the study is to track iron-oxide nanoparticle-labelled adult rat bone marrow-derived stem cells (IO-rBMSCs) by magnetic resonance imaging (MRI) and determine their effect in host cardiac tissue using 2-deoxy-2-[F-18]fluoro-D: -glucose-positron emission tomography (FDG-PET).
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A new model for prediction of drug distribution in tumor and normal tissues: pharmacokinetics of temozolomide in glioma patients.
Cancer Res.
PUBLISHED: 01-02-2009
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Difficulties in direct measurement of drug concentrations in human tissues have hampered the understanding of drug accumulation in tumors and normal tissues. We propose a new system analysis modeling approach to characterize drug distribution in tissues based on human positron emission tomography (PET) data. The PET system analysis method was applied to temozolomide, an important alkylating agent used in the treatment of brain tumors, as part of standard temozolomide treatment regimens in patients. The system analysis technique, embodied in the convolution integral, generated an impulse response function that, when convolved with temozolomide plasma concentration input functions, yielded predicted normal brain and brain tumor temozolomide concentration profiles for different temozolomide dosing regimens (75-200 mg/m(2)/d). Predicted peak concentrations of temozolomide ranged from 2.9 to 6.7 microg/mL in human glioma tumors and from 1.8 to 3.7 microg/mL in normal brain, with the total drug exposure, as indicated by the tissue/plasma area under the curve ratio, being about 1.3 in tumor compared with 0.9 in normal brain. The higher temozolomide exposures in brain tumor relative to normal brain were attributed to breakdown of the blood-brain barrier and possibly secondary to increased intratumoral angiogenesis. Overall, the method is considered a robust tool to analyze and predict tissue drug concentrations to help select the most rational dosing schedules.
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Comparative assessment of segmentation algorithms for tumor delineation on a test-retest [(11)C]choline dataset.
Med Phys
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Many methods have been proposed for tumor segmentation from positron emission tomography images. Because of the increasingly important role that [(11)C]choline is playing in oncology and because no study has compared segmentation methods on this tracer, the authors assessed several segmentation algorithms on a [(11)C]choline test-retest dataset.
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Development of a novel molecular sensor for imaging estrogen receptor-coactivator protein-protein interactions.
PLoS ONE
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Anti-estrogens, in particular tissue selective anti-estrogens, have been the bedrock of adjuvant therapy for patients with estrogen receptor alpha (ER?) positive breast cancer. Though current therapies have greatly enhanced patient prognosis, there continues to be an impetus for the development of improved anti-estrogens. ER? is a nuclear receptor transcription factor which activates gene expression through the recruitment of transcriptional coactivator proteins. The SRC family of coactivators, which includes AIB1, has been shown to be of particular importance for ER? mediated transcription. ER?-AIB1 interactions are indicative of gene expression and are inhibited by anti-estrogen treatment. We have exploited the interaction between ER? and AIB1 as a novel method for imaging ER? activity using a split luciferase molecular sensor. By producing a range of ER? ligand binding domain (ER-LBD) and AIB1 nuclear receptor interacting domain (AIB-RID) N- and C-terminal firefly luciferase fragment fusion proteins, constructs which exhibited more than a 10-fold increase in luciferase activity with E2 stimulation were identified. The specificity of the E2-stimulated luciferase activity to ER?-AIB1 interaction was validated through Y537S and L539/540A ER-LBD fusion protein mutants. The primed nature of the split luciferase assay allowed changes in ER? activity, with respect to the protein-protein interactions preceding transcription, to be assessed soon after drug treatment. The novel assay split luciferase detailed in this report enabled modulation of ER? activity to be sensitively imaged in vitro and in living subjects and potentially holds much promise for imaging the efficacy of novel ER? specific therapies.
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New frontiers in the design and synthesis of imaging probes for PET oncology: current challenges and future directions.
Mol Imaging Biol
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Despite being developed over 30 years ago, 2-deoxy-2-[(18)F]fluoro-D-glucose remains the most frequently used radiotracer in PET oncology. In the last decade, interest in new and more specific radiotracers for imaging biological processes of oncologic interest has increased exponentially. This review summarizes the strategies underlying the development of those probes together with their validation and status of clinical translation; a brief summary of new radiochemistry strategies applicable to PET imaging is also included. The article finishes with a consideration of the challenges imaging scientists must overcome to bring about increased adoption of PET as a diagnostic or pharmacologic tool.
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Radiosynthesis and in vivo tumor uptake of 2-deoxy-2-[(18)F]fluoro-myo-inositol.
Bioorg. Med. Chem. Lett.
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Inositols play an important role in membrane lipid metabolism and mitogenic signaling of most cancer cells. There is paucity of data on the distribution of radiolabelled inositols. Based on work previously carried out on 1-deoxy-1-[(18)F]fluoro-scyllo-inositol ([(18)F]2), we began a program of work to label myo-inositol (2-deoxy-2-[(18)F]fluoro-myo-inositol, [(18)F]1), the most abundant inositol in cells. Fluorination of a triflate precursor 4 afforded the desired [(18)F]1 following deprotection with a radiochemical yield of 8% n.d.c. [(18)F]1 showed higher uptake in vivo in a human breast cancer xenograft model, MDA-MB-231, compared to [(18)F]2. Thus, we have developed a new inositol radiotracer that could have utility for studying inositol uptake in tumors.
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Automated GMP synthesis of [(18)F]ICMT-11 for in vivo imaging of caspase-3 activity.
Nucl. Med. Biol.
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Isatin-5-sulfonamide ([(18)F]ICMT-11) is a sub-nanomolar inhibitor of caspase-3 previously evaluated as an apoptosis imaging agent. Herein, an alternative radiosynthesis of [(18)F]ICMT-11 with increased purity and specific activity is presented. Finally, a GMP-applicable automated radiosynthesis of [(18)F]ICMT-11 is described.
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Imaging of cellular proliferation in liver metastasis by [18F]fluorothymidine positron emission tomography: effect of therapy.
Phys Med Biol
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Although [(18)F]fluorothymidine positron emission tomography (FLT-PET) permits estimation of tumor thymidine kinase-1 expression, and thus, cell proliferation, high physiological uptake of tracer in liver tissue can limit its utility. We evaluated FLT-PET combined with a temporal-intensity information-based voxel-clustering approach termed kinetic spatial filtering (FLT-PET(KSF)) for detecting drug response in liver metastases. FLT-PET and computed tomography data were collected from patients with confirmed breast or colorectal liver metastases before, and two weeks after the first cycle of chemotherapy. Changes in tumor FLT-PET and FLT-PET(KSF) variables were determined. Visual distinction between tumor and normal liver was seen in FLT-PET(KSF) images. Of the 33 metastases from 20 patients studied, 26 were visible after kinetic filtering. The net irreversible retention of the tracer (Ki; from unfiltered data) in the tumor, correlated strongly with tracer uptake when the imaging variable was an unfiltered average or maximal standardized uptake value, 60 min post-injection (SUV(60,av): r = 0.9, SUV(60,max): r = 0.7; p < 0.0001 for both) and occurrence of high intensity voxels derived from FLT-PET(KSF) (r = 0.7, p < 0.0001). Overall, a significant reduction in the imaging variables was seen in responders compared to non-responders; however, the two week time point selected for imaging was too early to allow prediction of long term clinical benefit from chemotherapy. FLT-PET and FLT-PET(KSF) detected changes in proliferation in liver metastases.
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Evaluation of 2-deoxy-2-[18F]fluoro-D-glucose- and 3-deoxy-3-[18F]fluorothymidine-positron emission tomography as biomarkers of therapy response in platinum-resistant ovarian cancer.
Mol Imaging Biol
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We evaluated whether 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) and 3-deoxy-3-[(18)F]fluorothymidine ([(18)F]FLT) positron emission tomography (PET) could be used as imaging biomarkers of platinum resensitization in ovarian cancer.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.