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  • 1
  • 2
    Keywords: analysis, ANGIOGENESIS, animal, animals, antiangiogenic therapy, BLOOD, BLOOD-FLOW, BLOOD-VESSELS, C
    Abstract: High-frequency volumetric Power Doppler ultrasound (HF-VPDU) captures flow-dependent signals in blood vessels and can be used to assess antiangiogenic therapy effects in rodent tumors. However, the sensitivity is limited to vessels larger than capillaries. Contrast-enhanced HF-VPDU reveals all perfused vessels by assessing stimulated acoustic emissions from disintegrating microbubbles. Thus, we investigated whether flow-sensitive and contrast-enhanced HF-VPDU can depict different vessel fractions and assess their early response to antiangiogenic therapy. Mice with A431 tumors were scanned before and after administration of polybutylcyanoacrylate microbubbles by HF-VPDU. Animals received either antiangiogenic treatment. (SU11248) or a control substance and were imaged repeatedly over 9 days. At each time point, tumors were removed for immunohistochemical analysis. During growth of untreated tumors, vascularization decreased correspondingly on flow-sensitive and contrast-enhanced scans. Treated tumors showed it significantly (P 〈 0.05) stronger decline in vascularization than controls, which was more pronounced in contrast-enhanced scans. Surprisingly, whereas vascularization remained low in contrast-enhanced scans, flow-sensitive ultrasound indicated a reincrease after day 6 with a higher vascularization than the controls at day 9. Histologic evaluation indicated that immature vessels degraded markedly on therapy, whereas large mature vessels on the tumor periphery were more therapy resistant and drew closer due to tumor shrinkage. In conclusion, contrast-enhanced HF-VPDU and flow-sensitive HF-VPDU are both capable of assessing the effects of antiangiogenic therapy. Because contrast-sensitive ultrasound is more sensitive for small immature vessels and flow-sensitive ultrasound mostly captures large vessels at the tumor periphery, the combination of both methods can pro-vide evidence of vascular maturity in tumors
    Type of Publication: Journal article published
    PubMed ID: 18757418
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  • 3
    Keywords: RECEPTOR ; ANGIOGENESIS ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; INHIBITOR ; tumor ; carcinoma ; CELL ; FACTOR RECEPTOR ; Germany ; IN-VIVO ; THERAPY ; tumor growth ; VIVO ; DENSITY ; imaging ; QUANTIFICATION ; TUMORS ; ACCUMULATION ; MICE ; LIGAND ; MARKER ; BIOMARKERS ; CONTRAST AGENT ; BINDING ; UP-REGULATION ; TUMOR PROGRESSION ; MARKERS ; LIGANDS ; tomography ; INTEGRIN ; squamous cell carcinoma ; SELECTION ; specificity ; TUMOR ANGIOGENESIS ; CANCER-THERAPY ; ultrasound ; MICROBUBBLES ; molecular ; MATRIX ; CELL CARCINOMA ; ONCOLOGY ; RE ; XENOGRAFTS ; TUMOR-GROWTH ; THERAPIES ; INCREASE ; endothelial cells ; antiangiogenic therapy ; technique ; USA ; vascular endothelial growth factor ; cancer research ; SQUAMOUS-CELL ; GROWTH-FACTOR-RECEPTOR ; matrix metalloproteinase ; MATRIX-METALLOPROTEINASE ; xenograft ; quantitative ; EMISSION ; ENDOTHELIAL GROWTH ; response ; EXCESS ; FACTOR-RECEPTOR ; growth factor ; cyanoacrylate ; vascular endothelial growth factor receptor
    Abstract: Molecular ultrasound is capable of elucidating the expression of angiogenic markers in vivo. However, the capability of the method for volumetric "multitarget quantification" and for the assessment of antiangiogenic therapy response has rather been investigated. Therefore, we generated cyanoacrylate microbubbles linked to vascular endothelial growth factor receptor 2 (VEGFR2) and alpha(v)beta(3) integrin binding ligands and quantified their accumulation in squamous cell carcinoma xenografts (HaCaT-ras-A-5RT3) in mice with the quantitative volumetric ultrasound scanning technique, sensitive particle acoustic quantification. Specificity of VEGFR2 and alpha(v)beta(3) integrin binding microbubbles was shown, and changes in marker expression during matrix metalloproteinase inhibitor treatment were investigated. In tumors, accumulation of targeted microbubbles was significantly higher compared with nonspecific ones and could be inhibited competitively by addition of the free ligand in excess. Also, multimarker imaging could successfully be done during the same imaging session. Molecular ultrasound further indicated a significant increase of VEGFR2 and alpha(v)beta(3) integrin expression during tumor growth and a considerable decrease in both marker densities after matrix metalloproteinase inhibitor treatment. Histologic data suggested that the increasing VEGFR2 and alpha(v)beta(3) integrin concentrations in tumors during growth are related to an up-regulation of its expression by the endothelial cells, whereas its decrease under therapy is more related to the decreasing relative vessel density. In conclusion, targeted ultrasound appears feasible for the longitudinal molecular profiling of tumor angiogenesis and for the sensitive assessment of therapy effects in vivo
    Type of Publication: Journal article published
    PubMed ID: 18202013
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  • 4
    Keywords: ANGIOGENESIS, BIOTIN, BLOOD, CELLS, CLEARANCE, CONTRAST AGENT, cyanoacrylate, ENDOTHELIAL GROWTH, FL
    Abstract: Objectives: To assess the pharmacodynamic behavior of cyanoacrylate, streptavidin-coated microbubbles (MBs) and to investigate their suitability for molecular ultrasound imaging. Materials and Methods: Biodistribution of MBs was analyzed in tumor-bearing mice using gamma-counting, immunohistochemistry, flow cytometry, and ultrasound. Further, vascular endothelial growth factor receptor 2-antibody coupled MBs were used to image tumor neovasculature. Results: After 1 minute 〉 90% of MBs were cleared from the blood and pooled in the lungs, liver, and spleen. Subsequently, within I hour a decent reincrease of MB-concentration was observed in the blood. The remaining MBs were removed by liver and spleen macrophages. About 30% of the phagocytosed MBs were intact after 48 hours. Shell fragments were found in the kidneys only. No relevant MB-accumulation was observed in tumors. In contrast, vascular endothelial growth factor receptor 2-specific MBs accumulated significantly within the tumor vasculature (P 〈 0.05). Conclusions: The pharmacokinetic behavior of streptavidin-coated cyanoacrylate MBs has been studied. In this context, the low amount of MBs in tumors after 〉 5 minutes is beneficial for specific targeting of angiogenesis
    Type of Publication: Journal article published
    PubMed ID: 18301312
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  • 5
    Keywords: ACCUMULATION, ADHESION, ALPHA(V)BETA(3), ANGIOGENESIS, animals, BEHAVIOR, BINDING, CANCER, CANCERS,
    Abstract: Individualized treatments with combination of radiotherapy and targeted drugs require knowledge about the behavior of molecular targets after irradiation. Angiogenic marker expression has been studied after conventional radiotherapy, but little is known about marker response to charged particles. For the very first time, we used molecular ultrasound imaging to intraindividually track changes in angiogenic marker expression after carbon ion irradiation in experimental tumors. Expression of intercellular adhesion molecule-1 (ICAM-1) and of alpha(v)beta(3)-integrin in subcutaneous AT-1 prostate cancers in rats treated with carbon ions (16 Gy) was studied using molecular ultrasound and immunohistochemistry. For this purpose, cyanoacrylate microbubbles were synthesized and linked to specific ligands. The accumulation of targeted microbubbles in tumors was quantified before and 36 hours after irradiation. In addition, tumor vascularization was analyzed using volumetric Doppler ultrasound. In tumors, the accumulation of targeted microbubbles was significantly higher than in nonspecific ones and could be inhibited competitively. Before irradiation, no difference in binding of alpha(v)beta(3)-integrin-specific or ICAM-1-specific microbubbles was observed in treated and untreated animals. After irradiation, however, treated animals showed a significantly higher binding of alpha(v)beta(3)-integrin-specific microbubbles and an enhanced binding of ICAM-1-specific microbubbles than untreated controls. In both groups, a decrease in vascularization occurred during tumor growth, but no significant difference was observed between irradiated and nonirradiated tumors. In conclusion, carbon ion irradiation upregulates ICAM-1 and alpha(v)beta(3)-integrin expression in tumor neovasculature. Molecular ultrasound can indicate the regulation of these markers and thus may help to identify the optimal drugs and time points in individualized therapy regimens
    Type of Publication: Journal article published
    PubMed ID: 19724679
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  • 6
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    German Medical Science; Düsseldorf, Köln
    In:  27. Deutscher Krebskongress; 20060322-20060326; Berlin; DOCPO126 /20060320/
    Publication Date: 2006-04-21
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 7
    Keywords: ANGIOGENESIS ; CANCER ; tumor ; BLOOD ; carcinoma ; Germany ; MODEL ; PERFUSION ; THERAPY ; imaging ; SYSTEM ; TOOL ; TUMORS ; MICE ; IMPACT ; immunohistochemistry ; sensitivity ; SONOGRAPHY ; CANCER-THERAPY ; ONCOLOGY ; XENOGRAFTS ; monitoring ; ENHANCEMENT ; methods ; contrast-enhanced ultrasound ; therapy monitoring ; Small-animal ; Type ; LOOP ; Dynamic contrast-enhanced ultrasound ; MIOT ; Post-processing
    Abstract: Our aim was to prospectively compare two post-processing techniques for dynamic contrast-enhanced ultrasound and to evaluate their impact for monitoring antiangiogenic therapy. Thus, mice with epidermoid carcinoma xenografts were examined during administration of polybutylcyanoacrylate-microbubbles using a small animal ultrasound system (40 MHz). Cine loops were acquired and analyzed using time-intensity (TI) and maximum intensity over time (MIOT) curves. Influences of fast (50 mu l/2 s) vs. slow (50 mu l/10 s) injection of microbubbles on both types of curves were investigated. Sensitivities of both methods for assessing effects of antiangiogenic treatment (SU11248) were examined. Correlative histological analysis was performed for vessel-density. Mann-Whitney test was used for statistical analysis. Microbubble injection rates significantly influenced upslope, time-to-peak and peak enhancement of conventional TI curves (p 〈 0.05) but had almost no impact on maximum enhancement of MIOT curves (representing relative blood volume). Additionally, maximum enhancement of MIOT curves captured antiangiogenic therapy effects more reliably and earlier (already after 1 day of therapy; p 〈 0.05) than peak enhancement of TI curves. Immunohistochemistry validated the significantly (p 〈 0.01) lower vessel densities in treated tumors and high correlation (R-2 = 0.95) between vessel-density and maximum enhancement of MIOT curves was observed. In conclusion, MIOT is less susceptible to variations of the injection's speed. It enables to assess changes of the relative blood volume earlier and with lower standard deviations than conventional TI curves. It can easily be translated into clinical practice and thus may provide a promising tool for cancer therapy monitoring. (C) 2009 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 19945241
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  • 8
    ISSN: 1432-1084
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. A novel ultrasonic imaging method, wideband harmonic imaging, for nonlinear imaging of microbubble contrast agents is evaluated. In wideband harmonic mode, two pulses of alternate phase are send out. The image is then processed from the sum of both pulses, resulting in an image of nonlinear scatterers such as microbubbles. A prototype ultrasound system, Siemens Elegra, was evaluated with in vitro investigations and animal trials, using conventional, harmonic and wideband harmonic settings with the galactose based ultrasound contrast agent Levovist. Wideband harmonic imaging offers superior sensitivity for ultrasound contrast agents compared to conventional imaging and harmonic imaging. At low transmit power settings (MI 0.1–0.5) the nonlinear response is already sufficient to generate a image of the blood pool distribution of Levovist in the rabbit kidney including the microvasculature, with clear delineation of vessels and perfused parenchyma. At high transmit amplitudes, nonlinear tissue response reduced the apparent image contrast between contrast agent and tissue. The results suggest that wideband harmonic imaging is currently the most sensitive contrast imaging technique, maintaining highest spatial resolution. This may add to image quality and offer new clinical potential for the use of ultrasound contrast agents such as Levovist.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-1335
    Keywords: Droloxifene ; Endocrine-acting drugs ; NMU-induced rat mammary carcinoma ; oestradiol receptor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary InN-nitrosomethylurea-induced rat mammary tumours, tamoxifen is found to compete at the binding sites of the oestradiol receptor if a receptor determination is performed 1 day following the last drug application to animals. Despite a higher binding affinity of droloxifene (3-OH-tamoxifen) to oestradiol receptor, compared to tamoxifen, its influence on the measurable receptor quantity is only very weak or not demonstrable. Therefore, binding affinity is not a valid explanation for the different influences of the two anti-oestrogens on the receptor. These only can be attributed to different behaviour patterns of both substances in relation to their half-lives and metabolism and accumulation in the organism. Owing to the short half-life of droloxifene, even 1 day after the last application too little drug is available to compete for oestradiol binding sites. In the case of both anti-oestrogenic substances, cessation of drug application for 8 weeks abolished any influence on the oestradiol receptor. Furthermore, failure of aminoglutethimide to influence the oestradiol receptor could be observed because this substance does not act via this receptor. The experiments performed confirm literature data regarding the effect of aminoglutethimide therapy on oestradiol receptors breast tumour tissue of human beings. In summary: receptor investigations ofN-nitrosomethylurea-induced rat mammary tumours, used as a model to test therapy regimens with droloxifene or other drugs with a short half-life, may be of limited value only.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-1335
    Keywords: NMU-induced rat mammary tumours ; Hormonal manipulation ; Droloxifene ; Tumour growth behaviour
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effect of droloxifene, a new anti-oestrogenic drug, onN-nitrosomethylurea-induced mammary tumours of Sprague-Dawley rats was investigated and compared with that of tamoxifen. The response of tumour growth to ovariectomy or to treatment with aminoglutethimide or high doses of oestradiol was also studied. Ovariectomy was by far the most effective treatment for mammary-tumour-bearing animals. More than 75% of the tumours in ovariectomized rats did not grow progressively but remained in remission for up to 12 weeks after castration when the experiment was terminated. The inhibitory effects of droloxifene and tamoxifen on mammary tumour growth were similar, but body weight loss of animals treated with tamoxifen was more marked than that of animals treated with droloxifene at the same dose and schedule.
    Type of Medium: Electronic Resource
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