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  1. Article: Effects of vascular endothelial growth factor receptor inhibitor SU5416 and prostacyclin on murine lung metastasis.

    Cuneo, Kyle C / Fu, Allie / Osusky, Katherine L / Geng, Ling

    Anti-cancer drugs

    2007  Volume 18, Issue 3, Page(s) 349–355

    Abstract: The majority of patients with a diagnosis of cancer die from metastatic disease. Targeting specific steps in the metastatic process has the potential to improve patient outcomes. In this study, a novel lung metastasis model was developed by injecting DiI ...

    Abstract The majority of patients with a diagnosis of cancer die from metastatic disease. Targeting specific steps in the metastatic process has the potential to improve patient outcomes. In this study, a novel lung metastasis model was developed by injecting DiI (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbo-cyanine perchlorate)-labeled Lewis lung carcinoma cells into the tail vein of mice. The temporal development of tumor metastases was studied in the lung, liver and spleen. Additionally, the effects of vascular endothelial growth factor receptor inhibitor SU5416 and platelet activation inhibitor prostacyclin were tested in this metastasis model. Systemically injected Lewis lung carcinoma cells present in the lung at 15 min slowly accumulated in the liver and spleen reaching a peak at 4 days. After 8 days, tumor development was only evident in the lung. Use of SU5416 or prostacyclin lowered the initial density of Lewis lung carcinoma-labeled cells in the lung by a factor 1.8 and 2.3, respectively (P<0.05). Furthermore, treatment with prostacyclin or SU5416 decreased lung weight by over 50% and the number of visible metastatic nodes by over 90% (P<0.05). Combined treatment resulted in grossly normal lung tissue. Additionally, systemic treatment with prostacyclin reduced harvested metastatic cell adherence to endothelial cells by a factor of 10 and treatment with SU5416 attenuated vascular formation (P<0.001). In conclusion, SU5416 and prostacyclin effectively attenuated metastasis formation in this model. DiI labeling is an effective technique to monitor the temporal and spatial distribution of metastatic cells.
    MeSH term(s) Animals ; Carcinoma, Lewis Lung/drug therapy ; Carcinoma, Lewis Lung/pathology ; Cell Adhesion ; Cells, Cultured ; Disease Progression ; Epoprostenol/therapeutic use ; Indoles/therapeutic use ; Liver Neoplasms/drug therapy ; Liver Neoplasms/secondary ; Lung Neoplasms/drug therapy ; Lung Neoplasms/pathology ; Mice ; Mice, Inbred C57BL ; Neoplasm Metastasis/drug therapy ; Neoplasm Metastasis/pathology ; Neoplasm Transplantation ; Pyrroles/therapeutic use ; Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors ; Splenic Neoplasms/drug therapy ; Splenic Neoplasms/secondary
    Chemical Substances Indoles ; Pyrroles ; Semaxinib (71IA9S35AJ) ; Epoprostenol (DCR9Z582X0) ; Receptors, Vascular Endothelial Growth Factor (EC 2.7.10.1)
    Language English
    Publishing date 2007-03
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1065301-6
    ISSN 1473-5741 ; 0959-4973
    ISSN (online) 1473-5741
    ISSN 0959-4973
    DOI 10.1097/CAD.0b013e328011fdab
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3125: Show issues Location:
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  2. Article: The receptor tyrosine kinase inhibitor SU11248 impedes endothelial cell migration, tubule formation, and blood vessel formation in vivo, but has little effect on existing tumor vessels.

    Osusky, Katherine L / Hallahan, Dennis E / Fu, Allie / Ye, Fei / Shyr, Yu / Geng, Ling

    Angiogenesis

    2004  Volume 7, Issue 3, Page(s) 225–233

    Abstract: Antiangiogenic agents produce regression in few tumors in clinical trials, but are effective in preventing recurrences. To determine whether the vascular endothelial growth factor (VEGF) receptor is a molecular target to prevent metastatic disease, we ... ...

    Abstract Antiangiogenic agents produce regression in few tumors in clinical trials, but are effective in preventing recurrences. To determine whether the vascular endothelial growth factor (VEGF) receptor is a molecular target to prevent metastatic disease, we utilized a non-specific inhibitor of the VEGF receptor, SU11248. This receptor tyrosine kinase (RTK) inhibitor prevented migration of endothelial cells and markedly attenuated capillary-like tubule formation in endothelial cells in culture. Similarly, this agent prevented blood vessel formation in the tumor vascular window model. VEGF RTK inhibition produced minimal effects on established blood vessels in the tumor vascular window model and little effect on blood flow studied by power Doppler analysis. To determine whether these agents attenuate the development of metastases, Lewis lung carcinoma tumors were resected from the dorsal skin and lung metastases were quantified with and without treatment with SU11248. The RTK inhibitor attenuated the formation of lung metastases following resection of the hind limb tumor. In contrast, these agents did not induce regression of primaries but slowed the progression of tumor growth. These findings suggest that the greatest role for VEGF antagonists may be to prevent the formation of new blood vessels, during and after conventional therapy is given to existing neoplastic disease.
    MeSH term(s) Angiogenesis Inhibitors/pharmacology ; Angiogenesis Inhibitors/therapeutic use ; Animals ; Apoptosis ; Blood Vessels/drug effects ; Carcinoma, Lewis Lung/blood supply ; Carcinoma, Lewis Lung/drug therapy ; Cell Movement/drug effects ; Cells, Cultured ; Endothelium, Vascular/drug effects ; Endothelium, Vascular/physiology ; Humans ; Indoles/pharmacology ; Indoles/therapeutic use ; Intracellular Signaling Peptides and Proteins/pharmacology ; Intracellular Signaling Peptides and Proteins/therapeutic use ; Mice ; Mice, Inbred C57BL ; Neoplasm Metastasis/prevention & control ; Neovascularization, Pathologic/drug therapy ; Pyrroles/pharmacology ; Pyrroles/therapeutic use ; Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors ; Secondary Prevention ; Umbilical Cord/cytology
    Chemical Substances Angiogenesis Inhibitors ; Indoles ; Intracellular Signaling Peptides and Proteins ; Pyrroles ; protein kinase modulator ; Receptors, Vascular Endothelial Growth Factor (EC 2.7.10.1) ; sunitinib (V99T50803M)
    Language English
    Publishing date 2004
    Publishing country Germany
    Document type Journal Article ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 1484717-6
    ISSN 0969-6970
    ISSN 0969-6970
    DOI 10.1007/s10456-004-3149-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5094: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article: Radiation-guided drug delivery to tumor blood vessels results in improved tumor growth delay.

    Geng, Ling / Osusky, Katherine / Konjeti, Sekhar / Fu, Allie / Hallahan, Dennis

    Journal of controlled release : official journal of the Controlled Release Society

    2004  Volume 99, Issue 3, Page(s) 369–381

    Abstract: Tumor blood vessels are biological targets for cancer therapy. In this study, a tumor vasculature targeting system that consisted of liposomes and lectin (WGA) was built. Liposomes were used to carry a number of liposome-friendly anti-tumoral agents ... ...

    Abstract Tumor blood vessels are biological targets for cancer therapy. In this study, a tumor vasculature targeting system that consisted of liposomes and lectin (WGA) was built. Liposomes were used to carry a number of liposome-friendly anti-tumoral agents along with WGA, a lectin which posseses a specific affinity for binding to inflamed endothelial cells. In order to target tumor vasculature, inflammation of endothelial cells was induced by radiation. Because ionizing radiation induces an inflammatory response in tumor vasculature, lectin-conjugates were utilized to determine whether radiation can be used to target drug delivery to tumor vessels. Wheat germ agglutinin (WGA) is one such lectin that binds to inflamed microvasculature. WGA was conjugated to liposomes containing cisplatin and administered to tumor bearing mice. Tumor growth delay was used to analyze the efficacy of cytotoxicity. FITC-conjugated WGA accumulated within irradiated tumor microvasculature. WGA was conjugated to liposomes and labeled with 111In. This demonstrated radiation-inducible tumor-selective binding. WGA-liposome-conjugates were loaded with Cisplatin and administered to mice bearing irradiated tumors. Tumors treated with a combination of liposome encapsulated cisplatin together with radiation showed a significant increase in tumor growth delay as compared to radiation alone. These findings demonstrate that ionizing radiation can be used to guide drug delivery to tumor microvasculature.
    MeSH term(s) Angiogenesis Inhibitors/chemistry ; Angiogenesis Inhibitors/pharmacology ; Animals ; Cisplatin/pharmacology ; Combined Modality Therapy/methods ; Disease Models, Animal ; Drug Delivery Systems/methods ; Drug Screening Assays, Antitumor/methods ; Female ; Fluorescein-5-isothiocyanate/analogs & derivatives ; Fluorescein-5-isothiocyanate/metabolism ; Fluorescein-5-isothiocyanate/pharmacology ; Indium Radioisotopes ; Liposomes/chemistry ; Liposomes/metabolism ; Liposomes/pharmacology ; Mice ; Mice, Inbred C57BL ; Neoplasms/radiotherapy ; Neoplasms, Experimental/blood supply ; Neoplasms, Experimental/radiotherapy ; Neoplasms, Experimental/ultrastructure ; Neutron Capture Therapy ; Radiation-Sensitizing Agents/pharmacology ; Radiometry/adverse effects ; Radiometry/methods ; Skin/blood supply ; Skin/drug effects ; Skin/ultrastructure ; Tumor Cells, Cultured ; Wheat Germ Agglutinins/metabolism ; Wheat Germ Agglutinins/pharmacology
    Chemical Substances Angiogenesis Inhibitors ; Indium Radioisotopes ; Liposomes ; Radiation-Sensitizing Agents ; Wheat Germ Agglutinins ; fluorescein isothiocyanate-wheat germ agglutinin ; Fluorescein-5-isothiocyanate (I223NX31W9) ; Cisplatin (Q20Q21Q62J)
    Language English
    Publishing date 2004-10-19
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 632533-6
    ISSN 1873-4995 ; 0168-3659
    ISSN (online) 1873-4995
    ISSN 0168-3659
    DOI 10.1016/j.jconrel.2004.07.024
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 2055: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Article: Histone deacetylase inhibitor NVP-LAQ824 sensitizes human nonsmall cell lung cancer to the cytotoxic effects of ionizing radiation.

    Cuneo, Kyle C / Fu, Allie / Osusky, Katherine / Huamani, Jessica / Hallahan, Dennis E / Geng, Ling

    Anti-cancer drugs

    2007  Volume 18, Issue 7, Page(s) 793–800

    Abstract: Stage III nonsmall cell lung cancer is primarily treated with combined chemotherapy and radiation therapy. Relapses for progression of disease within irradiated sites remains a primary pattern of failure. To evaluate the interaction between histone ... ...

    Abstract Stage III nonsmall cell lung cancer is primarily treated with combined chemotherapy and radiation therapy. Relapses for progression of disease within irradiated sites remains a primary pattern of failure. To evaluate the interaction between histone deacetylase inhibitors and irradiation in nonsmall cell lung cancer, we studied NVP-LAQ824 in mouse models of human lung cancer. Colony formation assays were performed to determine whether LAQ824 sensitized nonsmall cell lung cancer to the cytotoxic effects of ionizing radiation. LAQ824 reduced clonogenic survival of the H23 and H460 cell lines five-fold compared with controls and four-fold compared with either agent alone (P<0.001). Western blot analysis of caspase cleavage, microscopic analysis of nuclei and Annexin-fluorescein isothiocyanate/propidium iodide flow cytometry assays showed that LAQ824 enhanced radiation-induced apoptosis and attenuated mitosis (P<0.001). Immunostaining for gamma-H2AX nuclear foci was performed to determine the effect of LAQ824 on radiation-induced DNA double-strand breaks. Combined modality treatment delayed the resolution of gamma-H2AX foci with over 30% of cells staining positive 6 h after treatment versus approximately 5 and 3% in cells treated with LAQ824 or radiation alone (P<0.001). Additionally, an in-vivo xenograft model was utilized to study the effects of fractioned irradiation and LAQ824 on tumor growth. Fractioned irradiation and LAQ824 delayed tumor growth by 19 days versus 7 and 4 days for treatment with LAQ824 and radiation alone. This study shows the effectiveness of histone deacetylase inhibitors to enhance the cytotoxic effects of radiation by attenuating DNA repair and inducing apoptosis in human nonsmall cell lung cancer.
    MeSH term(s) Animals ; Apoptosis/drug effects ; Apoptosis/radiation effects ; Blotting, Western ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/radiotherapy ; Cell Line, Tumor ; Colony-Forming Units Assay ; Combined Modality Therapy ; DNA Breaks, Double-Stranded/drug effects ; DNA Breaks, Double-Stranded/radiation effects ; DNA Repair/drug effects ; DNA Repair/radiation effects ; Disease Models, Animal ; Flow Cytometry ; Histone Deacetylase Inhibitors ; Histones/analysis ; Humans ; Hydroxamic Acids/pharmacology ; Lung Neoplasms/drug therapy ; Lung Neoplasms/radiotherapy ; Mice ; Mitosis/drug effects ; Mitosis/radiation effects ; Radiation, Ionizing ; Radiation-Sensitizing Agents/pharmacology ; Xenograft Model Antitumor Assays
    Chemical Substances H2AX protein, human ; Histone Deacetylase Inhibitors ; Histones ; Hydroxamic Acids ; LAQ824 ; Radiation-Sensitizing Agents
    Language English
    Publishing date 2007-06-20
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1065301-6
    ISSN 1473-5741 ; 0959-4973
    ISSN (online) 1473-5741
    ISSN 0959-4973
    DOI 10.1097/CAD.0b013e3280b10d57
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3125: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  5. Article: SRC family kinase inhibitor SU6656 enhances antiangiogenic effect of irradiation.

    Cuneo, Kyle C / Geng, Ling / Tan, Jiahuai / Brousal, Jeffrey / Shinohara, Eric T / Osusky, Katherine / Fu, Allie / Shyr, Yu / Wu, Huiyun / Hallahan, Dennis E

    International journal of radiation oncology, biology, physics

    2006  Volume 64, Issue 4, Page(s) 1197–1203

    Abstract: Purpose: Src family kinases (SFK) have been identified as molecular targets. SU6656 is a small-molecle indolinone that specifically inhibits this family of kinases.: Methods and materials: Human umbilical vein endothelial cells were used to study the ...

    Abstract Purpose: Src family kinases (SFK) have been identified as molecular targets. SU6656 is a small-molecle indolinone that specifically inhibits this family of kinases.
    Methods and materials: Human umbilical vein endothelial cells were used to study the effects of SFK inhibition. Western blot analysis was performed to determine the effect of SFK inhibition on the PI3K/Akt pathway and caspase cleavage. Apoptosis was studied by propidium iodide staining of nuclei. Angiogenesis was examined using capillary tubule formation in Matrigel. Tumor response was further studied in vivo using Lewis lung carcinoma cells implanted into the dorsal skin fold of mice in the window model and in the hind limb in the tumor volume model.
    Results: Clonogenic survival of endothelial cells was decreased after the combined therapy of SU6656 and radiation compared with radiotherapy alone. Furthermore, SFK inhibition by SU6656 attenuated radiation-induced Akt phosphorylation and increased radiation-induced apoptosis and vascular endothelium destruction. In vivo, SU6656 administered before irradiation significantly enhanced radiation-induced destruction of blood vessels within the tumor windows and enhanced tumor growth delay when administered during fractionated irradiation.
    Conclusions: This study demonstrates the potential use of SFK inhibition to enhance the effects of ionizing radiation during radiotherapy.
    MeSH term(s) Angiogenesis Inhibitors/pharmacology ; Animals ; Apoptosis ; Carcinoma, Lewis Lung/pathology ; Carcinoma, Lewis Lung/radiotherapy ; Caspases/metabolism ; Cell Count ; Class I Phosphatidylinositol 3-Kinases ; Endothelial Cells/cytology ; Endothelial Cells/drug effects ; Endothelial Cells/radiation effects ; Endothelium, Vascular/drug effects ; Endothelium, Vascular/metabolism ; Endothelium, Vascular/radiation effects ; Humans ; Indoles/pharmacology ; Mice ; Mice, Inbred C57BL ; Phosphatidylinositol 3-Kinases ; Phosphorylation ; Proto-Oncogene Proteins c-akt/metabolism ; Radiation-Sensitizing Agents/pharmacology ; Sulfonamides/pharmacology ; Umbilical Veins ; src-Family Kinases/antagonists & inhibitors
    Chemical Substances Angiogenesis Inhibitors ; Indoles ; Radiation-Sensitizing Agents ; SU 6656 ; Sulfonamides ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Class I Phosphatidylinositol 3-Kinases (EC 2.7.1.137) ; PIK3CA protein, human (EC 2.7.1.137) ; src-Family Kinases (EC 2.7.10.2) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Caspases (EC 3.4.22.-)
    Language English
    Publishing date 2006-03-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 197614-x
    ISSN 1879-355X ; 0360-3016
    ISSN (online) 1879-355X
    ISSN 0360-3016
    DOI 10.1016/j.ijrobp.2005.11.014
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1218: Show issues Location:
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