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    Keywords: CELLS ; EXPRESSION ; INHIBITOR ; tumor ; IN-VIVO ; GENE ; TUMORS ; ACCUMULATION ; CATECHOLAMINES ; gene therapy ; human norepinephrine transporter ; I-123 MIBG ; LINES ; METAIODOBENZYLGUANIDINE UPTAKE ; MIBG uptake ; MICE ; NEUROBLASTOMA-CELLS ; NORADRENALINE TRANSPORTER ; NUCLEAR-MEDICINE ; radiation ; RELEASE ; STORAGE ; TIME ; TRANSDUCTION
    Abstract: The transport of MIBG by the human norepinephrine transporter (hNET) seems to be the critical step in the treatment of MIBG- concentrating tumors. Therefore, we investigated whether the accumulation of MIBG may be induced by retroviral transect on of the hNET gene in Morris hepatoma cells. Methods: A bicistronic retroviral vector for the transfer of the hNET coding sequence and the hygromycin resistance gene was generated. Morris hepatoma cells (MH3924A) were infected with the respective retroviral particles, and hNET-expressing cell lines MHhNEThyg1 to MHhNEThyg9 were obtained through hygromycin selection. The uptake of H-3-norepinephrine or I-131-MIBG and the efflux of I-131-MIBG were determined in transfected and wild-type cells. In addition, the I-131-MIBG distribution was monitored in nude mice and rats bearing wild-type and hNET- expressing hepatomas. Results: hNET-expressing hepatoma cell lines accumulated up to 36 times more norepinephrine than did wild-type cells and 8 times more than did hNET-expressing neuroblastoma cell line SK-N-SH. The addition of nisoxetine, a selective inhibitor of noradrenaline uptake, inhibited norepinephrine uptake. Maximal I-131-MIBG accumulation was observed 2 h after incubation and was followed by 43% efflux within 4 h after the I-131-MIBG-containing medium had been removed. In vivo experiments performed with nude mice bearing both hNET-expressing and wild-type tumors showed a 10-fold- higher accumulation of I-131-MIBG in transfected tumors than in wild-type tumors. The ex vivo calculations revealed doses of 605 and 75 mGy in hNET-expressing and wild-type tumor tissues, respectively. Conclusion: Transduction of the hNET gene enables Morris hepatoma cells to accumulate norepinephrine and MIBG. However, the retention of MIBG is brief; therefore, the absorbed dose of radiation in vivo is not expected to be therapeutically effective
    Type of Publication: Journal article published
    PubMed ID: 12791828
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    Keywords: ACID, BINDING, BIOLOGICAL EVALUATION, CELLS, DIAGNOSIS, FOCI, hormone, imaging, INJECTION, IN-VITRO,
    Abstract: Although F-18-FDG PET is widely used for metastatic melanoma diagnosis, it is less accurate than desirable, particularly for small foci. Since both melanotic and amelanotic melanomas overexpress receptors for a-melanocyte-stimulating hormone (alpha-MSH; receptor name, melanocortin type 1 receptor [MC1 R]), radiolabeled alpha-MSH analogs are potential candidates for melanoma diagnosis. The aim of this study was to develop a positron emitter-labeled a-MSH analog suitable for PET imaging of melanoma metastases. Methods: A short linear alpha-MSH analog, [NIe(4),Asp(5),D-Phe(7)]-alpha-MSH4-11 (NAPamide), was newly designed and conjugated to the metal chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) to enable radiometal incorporation. Compared with our previously reported DOTA-alpha-MSH analog, DOTA-MSHoct ([DOTA-betaAla(3),NIe(4),Asp(5),DPhe(7),Lys(10)]-alpha-MSH3-10), the major modification lies in the conjugation of DOTA to the C-terminal end of the peptide via the E-amino group of Lys(11), as opposed to the N-terminal alpha-amino group. After labeling with In-111, Ga-67, and the short-lived positron emitter Ga-68, DOTA-NAPamide was characterized in vitro and in vivo using the mouse melanoma B16F1cell line. Results: DOTA-NAPamide exhibited an almost 7-fold higher MC1R binding potency as compared with DOTA-MSHoct. In B16F1 melanoma-bearing mice, both (111)in-DOTA-NAPamide and Ga-67-DOTA-NAPamide behaved more favorably than (111)InDOTA-MSHoct. Both radiopeptides exhibited higher tumor and lower kidney uptake leading to tumor-to-kidney ratios of the 4-to 48-h area under the curve that were 4.6 times (In-111) and 7.5 times (Ga-67) greater than that obtained with In-111-DOTA-MSHoct. In addition, the 4-h kidney uptake of Ga-67-DOTA-NAPamide could be reduced by 64% by coinjection of 15 Mg L-lysine, without affecting tumor uptake. Skin primary melanoma as well as lung and liver melanoma metastases could be easily visualized on tissue section autoradiographs after systemic injection of 67Ga-DOTA-NAPamide. The melanoma selectivity of DOTA-NAPamide was confirmed by PET imaging studies using (68)GaDOTA-NAPamide. Tumor uptake was found to be highest when the smallest amount of peptide was administered. Conclusion: DOTA-NAPamide labeled with either In-111 or Ga-67/Ga-68 is in every way superior to In-111-DOTA-MSHoct in murine models of
    Type of Publication: Journal article published
    PubMed ID: 14734683
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    Keywords: IRRADIATION ; radiotherapy ; tumor ; CLASSIFICATION ; TOOL ; METABOLISM ; DIFFERENTIATION ; NUCLEAR-MEDICINE ; radiation ; TIME ; PATIENT ; CONTRAST ; MR ; MRI ; PROTON ; SPECTROSCOPY ; ACID ; TRANSPORT ; PERFORMANCE ; stereotactic ; stereotactic radiotherapy ; LESIONS ; PROGRESSION ; RADIATION-THERAPY ; DIFFERENCE ; TUMOR PROGRESSION ; POSITRON-EMISSION-TOMOGRAPHY ; MORPHOLOGY ; PET ; TRACER ; ALPHA-METHYL TYROSINE ; IODINE-123-ALPHA-METHYL TYROSINE ; LOW-GRADE ASTROCYTOMA ; PRIMARY BRAIN-TUMORS ; RECURRENT GLIOMAS ; TC-99M SESTAMIBI ; TC-99M-SESTAMIBI
    Abstract: Differentiation between tumor progression and radiation necrosis is one of the most difficult tasks in oncologic neuroradiology. Functional imaging of tumor metabolism can help with this task, but the choice of tracer is still controversial. This prospective study following up irradiated low-grade astrocytoma (LGA) was, to our knowledge, the first receiver-operating-characteristic (ROC) analysis that intraindividually evaluated the diagnostic performance of the SPECT tracers 3-[I-123]iodo-alpha-methyl-L-tyrosine (IMT) and Tc-99m(I)-hexakis(2-methoxyisobutylisonitrile) (MIBI) and the PET tracer F-18-FDG. Methods: We examined 17 patients, initially with histologically proven LGA and treated by stereotactic radiotherapy, who presented with new gadolinium-diethylenetriaminepentaacetic acid-enhancing lesions (n = 26) on MRI. At that time, MRI could not differentiate between progressive tumor and nonprogressive tumor. This MRI examination was closely followed by F-18-FDG PET and by Tc-99m-MIBI and I-123-IMT SPECT. Lesions were classified as progressive tumor (n = 17) or nonprogressive tumor (n = 9) on the basis of prospective follow-up (through clinical examination, MRI, and proton MR spectroscopy) for 26.6 +/- 6.6 mo after PET or SPECT. Results: I-123-IMT yielded the best ROC characteristics and was the most accurate for classification, with an area under the ROC curve (A(z)) of 0.991. The A(z) of F-18-FDG (0.947) was not significantly lower than that of I-123-IMT. The difference in the A(z) of Tc-99m-MIBI (0.713) from the A(z) of the other tracers used in our study was highly significant (P : 0.01). Tc-99m-MIBI SPECT was of low accuracy and, especially, of poor sensitivity even at modest specificity values. Conclusion: I-123-IMT SPECT imaging of amino acid transport accurately detects tumor progression in patients with irradiated LGA. In contrast to I-123-IMT, F-18-FDG PET was slightly less accurate for classification, and Tc-99m-MIBI SPECT was of limited value. Imaging of amino acid transport with I-123-IMT is a valuable additional tool for the follow-up of LGA, allowing early, noninvasive differentiation of lesions with ambiguous morphology after irradiation
    Type of Publication: Journal article published
    PubMed ID: 15073253
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    Journal of Nuclear Medicine 46 (Suppl. 1), 172S-178S 
    Keywords: PEPTIDE ; RECEPTOR ; CANCER ; tumor ; IN-VIVO ; THERAPY ; VITRO ; GENERATION ; imaging ; TUMORS ; PATIENT ; ACID ; PROSTATE-CANCER ; DERIVATIVES ; PEPTIDES ; BIODISTRIBUTION ; PET ; sensitivity ; RECEPTORS ; targeting ; ONCOLOGY ; tumor imaging ; SOMATOSTATIN ANALOG ; SOMATOSTATIN RECEPTORS ; RECEPTOR-POSITIVE TUMORS ; neuroendocrine tumor ; SWITZERLAND ; RADIOPHARMACEUTICALS ; Ga-68 ; MELANOCYTE-STIMULATING HORMONE ; NEUROENDOCRINE TUMORS
    Abstract: Radiolabeled peptides are of increasing interest in nuclear oncology. Special emphasis has been given to the development of peptides labeled with positron emitters. Among these, Ga-68 deserves special attention, because it is available from an in-house generator rendering Ga-68 radiopharmacy independent of an onsite cyclotron. Ga-68 has a half-life of 68 min and decays by 89% through positron emission. The parent, Ge-68, is accelerator produced and decays with a half-life of 270.8 d by electron capture. Currently, at least 1 commercial and several in-house generators are available. 68Ge is strongly absorbed on metal oxides or organic material, making a Ge-68-breakthrough highly unlikely. Several groups continue to further develop generators to remove cationic impurities from the eluate. Several bifunctional chelators based on 1,4,7-triazacyclononane-N,N',N"-tri-acetic acid and 1,4,7,10-tetraazacyclododecane-NN',N",N"'-tetraacetic acid (DOTA) macrocycles are available for coupling to peptides and other biomolecules. In addition to these hydrophilic chelators, a lipophilic tetradentate S3N ligand was developed. Radiopeptides for Ga-68 labeling have been developed and tested preclinically for the targeting of somatostatin receptors, the melanocortin 1 receptor, and the bombesin receptor. Clinical studies were performed with Ga-68-DOTA,Tyr(3)-octreotide, localizing neuroendocrine tumors with higher sensitivity than In-111-diethylenetriaminepentaacetic acid-octreotide. In addition, Ga-68-DOTA-based bombesin derivatives are being investigated with some success in patients with prostate cancer. Conclusion: Generator-produced Ga-68 and the development of small chelator-coupled peptides (and other small biomolecules) may open a new generation of freeze-dried, good manufacturing practice-produced, kit-formulated PET radiopharmaceuticals similar to Mo-99-/Tc-99m-generator-based, Tc-99m-labeled radiopharmaceuticals
    Type of Publication: Journal article published
    PubMed ID: 15653666
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    Keywords: Germany ; SITES ; PROTEIN ; PROTEINS ; IMPACT ; CELL-DEATH ; Tc-99m ; RE ; ANNEXIN-V ; IN-VIVO DETECTION ; ANTICOAGULANT ; IMMUNOREACTIVITY ; MEMBRANE-BINDING ; PHOSPHATIDYLSERINE EXPRESSION
    Type of Publication: Journal article published
    PubMed ID: 16954544
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    Keywords: RECEPTOR ; ANGIOGENESIS ; APOPTOSIS ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; proliferation ; tumor ; carcinoma ; CELL ; CELL-PROLIFERATION ; ENDOTHELIAL GROWTH-FACTOR ; FACTOR RECEPTOR ; Germany ; human ; IN-VIVO ; MODEL ; PERFUSION ; imaging ; SYSTEM ; GENE ; GENES ; TUMORS ; gene therapy ; LINES ; gene transfer ; GENE-TRANSFER ; COMPLEX ; COMPLEXES ; DNA ; INDUCTION ; RAT ; ANTIGEN ; CELL-LINES ; signal transduction ; SIGNAL ; immunohistochemistry ; VECTOR ; NUMBER ; STRESS ; SIGNAL-TRANSDUCTION ; CELL-LINE ; LINE ; HEPATOMA ; EXTRACELLULAR-MATRIX ; PET ; RECEPTORS ; OXIDATIVE STRESS ; OVEREXPRESSION ; cell lines ; CELL-MIGRATION ; VASCULARIZATION ; VEGF ; HUMAN COLON-CANCER ; MATRIX ; OXIDATIVE-STRESS ; TUMOR-GROWTH ; INCREASE ; extracellular matrix ; ENHANCED EXPRESSION ; cell proliferation ; TUMOR PERFUSION ; MIGRATION INHIBITORY FACTOR ; CHIP ; functional imaging ; function ; GROWTH-FACTOR-RECEPTOR ; angiopoietin-2 ; TIE2 ; TUNEL ; UP-REGULATES ANGIOPOIETIN-2
    Abstract: Monitoring of angiogenesis-relevant approaches with functional imaging and histomorphometric analyses is desirable to evaluate the biologic effects. In this study we wished to examine the complex effects of angiopoietin-2 (Ang-2) gene transfer in a rat hepatoma model. Methods: Using a bicistronic retroviral vector for Ang-2, Morris hepatoma (MH3924A) cell lines with Ang-2 expression were generated (Ang-2-MH3924A). In human umbilical vein endothelial cells (HUVECs) cocultured with Ang-2MH3924A, the proliferative action with or without growth factors were determined. Furthermore, animal experiments were performed to measure effects on tumor growth and perfusion. Finally, tumors were examined by immunohistochemistry and DNA chip analysis. Results: Ang-2-expressing MH3924A enhanced basic fibroblast growth factor-mediated endothelial cell proliferation. Perfusion, as measured by (H2O)-O-15 PET, was increased in genetically modified tumors. Consistent with the increased perfusion, micro- and macrovascularization were increased. However, tumor growth was similar to wild-type MH3924A (WT-MH3924A). Proliferating cell nuclear antigen and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) staining revealed an increased number of positive cells, indicating a compensation of increased proliferation by enhanced apoptosis. DNA chip analysis showed an induction of angiogenesis-promoting genes, including crucial vascular growth factor receptors, as well as genes related to extracellular matrix (ECM), apoptosis, signal transduction, and oxidative stress. Conclusion: Our results suggest that Ang-2 expression increases perfusion or vascularization, especially in interaction with the vascular growth factor system, without affecting tumor growth. Simultaneous, enhanced expression of genes for ECM, apoptosis, and signal transduction indicates Ang-2's versatile role in angiogenesis including its destabilizing function on ECM and endothelium
    Type of Publication: Journal article published
    PubMed ID: 16954561
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    Keywords: brain ; RECEPTOR ; EXPRESSION ; tumor ; BLOOD ; evaluation ; Germany ; MODEL ; THERAPY ; DIAGNOSIS ; FOLLOW-UP ; imaging ; VOLUME ; DISEASE ; TISSUE ; TUMORS ; ACCUMULATION ; NUCLEAR-MEDICINE ; PATIENT ; IMPACT ; primary ; treatment ; ACID ; LESIONS ; PARAMETERS ; tomography ; MULTIVARIATE ; STOMACH ; SCINTIGRAPHY ; PET ; KINETICS ; RECURRENT ; nuclear medicine ; radiology ; RE ; THERAPIES ; F-18-FDG ; ANALOG ; TUMOR TISSUE ; IMATINIB MESYLATE ; analysis ; methods ; NUCLEAR ; USA ; GA-68-DOTATOC ; kinetic modeling ; uptake ; correlation ; EVALUATE ; multivariate analysis ; UNIT ; blood volume ; comparison ; Ga-68-bombesin ; GIST
    Abstract: Dynamic PET studies with a Ga-68-bombesin analog, DOTA-PEG(2)-[D-Tyr (6), beta-Ala(11),Thi(13) Nle(14)] BN(6-14) amide (Ga-68-BZH(3); DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N '',N'''-tetraacetic acid, and PEG is ethylene glycol [2-aminoethyl-carboxymethyl ether]), were performed on patients with gastrointestinal stromal tumors (GIST) to investigate the impact of complementary receptor scintigraphy on diagnosis and the potential of a radionuclide treatment. Furthermore, dynamic F-18-FDG studies were performed on the same patients. Methods: This study comprised 17 patients with GIST. All patients were scheduled for therapy with imatinib because of unresectable primary or recurrent GIST or because of metastatic disease. Dynamic PET scans using Ga-68-BZH(3) and F-18-FDG were obtained on 2 consecutive days. Multivariate analysis was used to evaluate the kinetic data. Standardized uptake values (SUVs) were calculated, and a compartmental model (2-tissue) and noncompartmental model were used for data evaluation of both tracers. Results: Fourteen of 17 patients (25/30 lesions) were positive for uptake on F-18-FDG imaging, whereas Ga-68-BZH(3) demonstrated an enhanced accumulation in 7 of 17 patients (8/30 lesions). Thirteen lesions were confirmed by histologic examination, and the remaining 17 were confirmed by follow-up. One recurrent tumor in the stomach could not be delineated on F-18-FDG imaging but showed enhanced Ga-68-BZH(3) uptake. The median SUV for Ga-68-BZH(3) was 3.3, in comparison with 7.9 for 18F-FDG. Best-subset analysis demonstrated that the global SUV (55-60 min after injection) for F-18-FDG was primarily dependent on k3, followed by k1. Multivariate analysis did not show a significant correlation between the kinetic parameters (kl-k4, fractional blood volume, and SUV) for F-18-FDG and bombesin. Conclusion: Ga-68-BZH(3) may be helpful for diagnostic reasons in a subgroup of patients with GIST, as in the case of negative F-18-FDG findings and suspicion of viable tumor tissue. The meaning of the enhanced Ga-68-BZH(3) uptake is open at the moment
    Type of Publication: Journal article published
    PubMed ID: 17631559
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