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      1. Author :
        Holland, Sacha J; Pan, Alison; Franci, Christian; Hu, Yuanming; Chang, Betty; Li, Weiqun; Duan, Matt; Torneros, Allan; Yu, Jiaxin; Heckrodt, Thilo J; Zhang, Jing; Ding, Pingyu; Apatira, Ayodele; Chua, Joanne; Brandt, Ralf; Pine, Polly; Goff, Dane; Singh, Rajinder; Payan, Donald G; Hitoshi, Yasumichi
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Cancer research
      6. Products :
      7. Volume :
        70
      8. Issue :
        4
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Antineoplastic Agents; Benzocycloheptenes; Bioware; Breast Neoplasms; Carcinoma; Female; Hela Cells; Humans; K562 Cells; MDA-MB-231-D3H2LN cells; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Oncogene Proteins; Protein kinase inhibitors; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Survival Analysis; Triazoles; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
      12. Abstract :
        Accumulating evidence suggests important roles for the receptor tyrosine kinase Axl in cancer progression, invasion, metastasis, drug resistance, and patient mortality, highlighting Axl as an attractive target for therapeutic development. We have generated and characterized a potent and selective small-molecule inhibitor, R428, that blocks the catalytic and procancerous activities of Axl. R428 inhibits Axl with low nanomolar activity and blocked Axl-dependent events, including Akt phosphorylation, breast cancer cell invasion, and proinflammatory cytokine production. Pharmacologic investigations revealed favorable exposure after oral administration such that R428-treated tumors displayed a dose-dependent reduction in expression of the cytokine granulocyte macrophage colony-stimulating factor and the epithelial-mesenchymal transition transcriptional regulator Snail. In support of an earlier study, R428 inhibited angiogenesis in corneal micropocket and tumor models. R428 administration reduced metastatic burden and extended survival in MDA-MB-231 intracardiac and 4T1 orthotopic (median survival, >80 days compared with 52 days; P < 0.05) mouse models of breast cancer metastasis. Additionally, R428 synergized with cisplatin to enhance suppression of liver micrometastasis. Our results show that Axl signaling regulates breast cancer metastasis at multiple levels in tumor cells and tumor stromal cells and that selective Axl blockade confers therapeutic value in prolonging survival of animals bearing metastatic tumors.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20145120
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8949
      1. Author :
        Quintela-Fandino, Miguel; Arpaia, Enrico; Brenner, Dirk; Goh, Theo; Yeung, Faith Au; Blaser, Heiko; Alexandrova, Roumiana; Lind, Evan F; Tusche, Mike W; Wakeham, Andrew; Ohashi, Pamela S; Mak, Tak W
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Proceedings of the National Academy of Sciences of the United States of America
      6. Products :
      7. Volume :
        107
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Actins; Animals; B16-F10-luc-G5; Bioware; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cofilin 1; Cytoskeleton; Female; Humans; Immunoblotting; Immunoprecipitation; Male; Mammary Neoplasms, Experimental; MDA-MB-231-D3H2LN cells; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Invasiveness; Neoplasm Metastasis; Phosphorylation; Protein Binding; Protein Kinases; Protein Phosphatase 2; Protein-Serine-Threonine Kinases; RNA Interference; Transplantation, Heterologous
      12. Abstract :
        Metastasis leads to the death of most cancer patients, and basal breast cancer is the most aggressive breast tumor type. Metastasis involves a complex cell migration process dependent on cytoskeletal remodeling such that targeting such remodeling in tumor cells could be clinically beneficial. Here we show that Hormonally Up-regulated Neu-associated Kinase (HUNK) is dramatically down-regulated in tumor samples and cell lines derived from basal breast cancers. Reconstitution of HUNK expression in basal breast cancer cell lines blocked actin polymerization and reduced cell motility, resulting in decreased metastases in two in vivo murine cancer models. Mechanistically, HUNK overexpression sustained the constitutive phosphorylation and inactivation of cofilin-1 (CFL-1), thereby blocking the incorporation of new actin monomers into actin filaments. HUNK reconstitution in basal breast cancer cell lines prevented protein phosphatase 2-A (PP2A), a phosphatase putatively acting on CFL-1, from binding to CFL-1. Our investigation of HUNK suggests that the interaction between PP2A and CFL-1 may be a target for antimetastasis therapy, particularly for basal breast cancers.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20133759
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8951
      1. Author :
        Korotcov, Alexandru; Shan, Liang; Meng, Huan; Wang, Tongxin; Sridhar, Rajagopalan; Zhao, Yuliang; Liang, Xing-Jie; Wang, Paul C
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Journal of nanoscience and nanotechnology
      6. Products :
      7. Volume :
        10
      8. Issue :
        11
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bioware; Contrast Media; Magnetic Resonance Imaging; Mice; Nanotechnology; PC-3M-luc
      12. Abstract :
        We have developed and tested a liposomal nanocomplex system, which contains Gd-DTPA as a payload and transferrin on the surface, as a tumor specific targeting MRI contrast agent for studying prostate cancer tumors in mice. In vivo, the probe significantly enhanced the MRI signal. The image contrast between the peripheral region of the tumor and the non-involved muscle was nearly 50% higher two hours after administration of the nanocomplex. The liposomal nanocomplex increased the amount of Gd accumulated in tumors by factor 2.8 compared to that accumulated by using Magnevist alone. Moreover, the heterogeneous MRI image features correlate well with the tumor pathology. The image enhancement patterns can be used for cancer prognosis and non-invasive monitoring of the response to therapy.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21137979
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8963
      1. Author :
        Neal, Robert E, 2nd; Singh, Ravi; Hatcher, Heather C; Kock, Nancy D; Torti, Suzy V; Davalos, Rafael V
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Breast cancer research and treatment
      6. Products :
      7. Volume :
        123
      8. Issue :
        1
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bioware; Cell Line, Tumor; Electrochemotherapy; Electrodes; Female; Humans; Mammary Neoplasms, Experimental; MDA-MB-231-D3H1 cells; Mice; Mice, Nude; Needles; Xenograft Model Antitumor Assays
      12. Abstract :
        Irreversible electroporation (IRE) is a therapeutic technology for the ablation of soft tissues using electrodes to deliver intense but short electric pulses across a cell membrane, creating nanopores that lead to cell death. This phenomenon only affects the cell membrane, leaving the extracellular matrix and sensitive structures intact, making it a promising technique for the treatment many types of tumors. In this paper, we present the first in vivo study to achieve tumor regression using a translatable, clinically relevant single needle electrode for treatment administration. Numerical models of the electric field distribution for the protocol used suggest that a 1000 V/cm field threshold is sufficient to treat a tumor, and that the electric field distribution will slightly decrease if the same protocol were used on a tumor deep seated within a human breast. Tumor regression was observed in 5 out of 7 MDA-MB231 human mammary tumors orthotopically implanted in female Nu/Nu mice, with continued growth in controls.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20191380
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8988
      1. Author :
        Nguyen, Leslie; Zhong, Wei-Zhu; Painter, Cory L; Zhang, Cathy; Rahavendran, Sadayappan V; Shen, Zhongzhou
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Journal of pharmaceutical and biomedical analysis
      6. Products :
      7. Volume :
        53
      8. Issue :
        3
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bioware; Chromatography, Liquid; Cyclin-Dependent Kinase 4; Drug Stability; Female; Humans; MDA-MB-231-D3H1 cells; Mice; Mice, SCID; Neoplasm Transplantation; Neoplasms, Experimental; Piperazines; Protein kinase inhibitors; Pyridines; Sensitivity and Specificity; Tandem Mass Spectrometry; Transplantation, Heterologous
      12. Abstract :
        Phase II attrition of clinical candidates in the drug development cycle is currently a major issue facing the pharmaceutical industry. To decrease phase II attrition, there is an increased emphasis on validation of mechanism of action, development of efficacy models and measurement of drug levels at the site of action. PD 0332991, a highly specific inhibitor of cyclin-dependent kinase 4 (CDK-4) is currently in clinical development for the treatment of solid tumor. A clinical presurgical study will be required to better understand how PD 0332991 affects signaling pathways and how the intratumoral concentration of PD 0332991 correlates with plasma PK parameters and molecular alterations in breast cancer tissues after PD 0332991 treatment. Before conducting such a clinical study, it is important to evaluate PD 0332991 levels in tumor tissue samples from a xenograft mouse model for the determination of drug exposure at the site of action. Therefore, the objectives of this study were (1) to develop and validate a sensitive LC-MS/MS method to quantify PD 0332991 in mouse tumor tissues from MDA-MB-231-Luc human breast tumor xenografts in SCID-beige mice; (2) to quantify PD 0332991 levels in mouse tumor tissues after oral administration of PD 0332991 at 10 and 100mg/kg using the validated LC-MS/MS method. Both liquid-liquid extraction (LLE) and supported liquid extraction (SLE) in a 96-well format were developed and evaluated to achieve optimal extraction recovery with minimal matrix effects. The newly developed SLE method is more efficient (speed and ease) and demonstrates comparable recovery (93.1-100% at three different concentrations) compared to the traditional LLE method. The validated LC-MS/MS for PD 032291 in mouse tumor tissue homogenate method exhibited a linear dynamic range of 0.1-100 ng/mL with inter-day accuracy and precision within 15%. The validated method was successfully applied to measure PD 0332991 levels in tumor tissues in MDA-MB-231-Luc human breast tumor xenografts in SCID beige mice. The mean tumor concentrations at 6h post-oral PD 0332991 administration at 10 and 100mg/kg were 1793 (+/-1008) and 25,163 (+/-3959) ng/g, respectively.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20236782
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8987
      1. Author :
        Zhang, H; Fagan, D H; Zeng, X; Freeman, K T; Sachdev, D; Yee, D
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Oncogene
      6. Products :
      7. Volume :
        29
      8. Issue :
        17
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Bioware; Cell Line, Tumor; Cell Proliferation; Female; Humans; Insulin; Lung Neoplasms; Lymphangiogenesis; MDA-MB-231-D3H1 cells; Mice; Neoplasm Metastasis; Neoplasms, Experimental; Neovascularization, Pathologic; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptor, Insulin; RNA, Small Interfering; Vascular Endothelial Growth Factor A
      12. Abstract :
        Insulin receptor (IR) and the type I IGF receptor (IGF1R) are structurally and functionally related. The function of IGF1R in cancer has been well documented and anti-IGF1R strategies to treat cancer have shown initial positive results. However, the role of IR in tumor biology, independent of IGF1R, is less clear. To address this issue, short hairpin RNA (shRNA) was used to specifically downregulate IR in two cancer cell lines, LCC6 and T47D. Cells with reduced IR showed reduced insulin-stimulated Akt activation, without affecting IGF1R activation. Cells with reduced IR formed fewer colonies in anchorage-independent conditions. LCC6 IR shRNA xenograft tumors in mice had reduced growth, angiogenesis and lymphangiogensis when compared with LCC6 wild-type cells. Accordingly, LCC6 IR shRNA clones produced less hypoxia-inducible factor-1alpha, vascular endothelial growth factor (VEGF)-A and VEGF-D. Furthermore, LCC6 IR shRNA cells formed fewer pulmonary metastases when compared with LCC6 wild-type cells. Using in vivo luciferase imaging, we have shown that LCC6 IR shRNA cells have less seeding and colonization potential in the lung and liver of mice than LCC6 cells. In conclusion, downregulation of IR inhibited cancer cell proliferation, angiogenesis, lymphangiogenesis and metastasis. Our data argue that IR should also be targeted in cancer therapy.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20154728
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8986
      1. Author :
        Luo, Z R; Huang, T; Li, W; Shen, B Z
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Panminerva medica
      6. Products :
      7. Volume :
        52
      8. Issue :
        1
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; B16-F10-luc-G5 cells; Bioware; Diagnostic Imaging; Luminescence; Melanoma, Experimental; Mice; Mice, Inbred BALB C; Molecular Dynamics Simulation
      12. Abstract :
        AIM The aim of this study was to evaluate the veracity and sensitivity of in-vivo imaging system (IVIS) for inspection of tumor dynamic morphology. METHODS Mouse melanoma cells (B16-F10-luc-G5) in 100 mL media were seeded into a 96-well plate by 1:2 serial dilution from 10000 cells (well #1) to 78 cells (well #8). The plate was imaged using IVIS system to evaluate its sensitivity for luminescence. Ten Bablc mice with tumor cells were injected subcutaneously (1 x 10(5) in 100 mL) and tumor luminescence was detected by IVIS at Day 0, Day 3, Day 5, Day 7 and Day 9. RESULTS As few as 78 tumor cells were detectable by IVIS. A strong correlation between number of tumor cells and bioluminescence (R2=0.99) was also demonstrated. Tumor luminescence were observed in all mice by IVIS at all days, and there was significant difference (P<0.01) between each two days from Day 0 to Day 9. Moreover, tumor dynamic morphology could be monitored by IVIS when it is invisible. CONCLUSION Compared with conventional methods, with high veracity and sensitivity, IVIS system should be recommended as an effective method for inspection of tumor dynamic morphology.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20228722
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8995
      1. Author :
        Marttila-Ichihara, Fumiko; Castermans, Karolien; Auvinen, Kaisa; Oude Egbrink, Mirjam G A; Jalkanen, Sirpa; Griffioen, Arjan W; Salmi, Marko
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Journal of immunology (Baltimore, Md.: 1950)
      6. Products :
      7. Volume :
        184
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Adjuvants, Immunologic; Allylamine; Amine Oxidase (Copper-Containing); Animals; Antibodies, Blocking; Antibodies, Monoclonal; B16-F10-luc-G5 cells; Bioware; Cell Adhesion Molecules; Cell Line, Tumor; Cell Migration Inhibition; Enzyme Inhibitors; Female; Growth Inhibitors; Lymphoma, T-Cell; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Myeloid Cells; Semicarbazides
      12. Abstract :
        Vascular adhesion protein-1 (VAP-1) is an endothelial, cell surface-expressed oxidase involved in leukocyte traffic. The adhesive function of VAP-1 can be blocked by anti-VAP-1 Abs and small-molecule inhibitors. However, the effects of VAP-1 blockade on antitumor immunity and tumor progression are unknown. In this paper, we used anti-VAP-1 mAbs and small-molecule inhibitors of VAP-1 in B16 melanoma and EL-4 lymphoma tumor models in C57BL/6 mice. Leukocyte accumulation into tumors and neoangiogenesis were evaluated by immunohistochemistry, flow cytometry, and intravital videomicroscopy. We found that both anti-VAP-1 Abs and VAP-1 inhibitors reduced the number of leukocytes in the tumors, but they targeted partially different leukocyte subpopulations. Anti-VAP-1 Abs selectively inhibited infiltration of CD8-positive lymphocytes into tumors and had no effect on accumulation of myeloid cells into tumors. In contrast, the VAP-1 inhibitors significantly reduced only the number of proangiogenic Gr-1(+)CD11b(+) myeloid cells in melanomas and lymphomas. Blocking of VAP-1 by either means left tumor homing of regulatory T cells and type 2 immune-suppressing monocytes/macrophages intact. Notably, VAP-1 inhibitors, but not anti-VAP-1 Abs, retarded the growth of melanomas and lymphomas and reduced tumor neoangiogenesis. The VAP-1 inhibitors also reduced the binding of Gr-1(+) myeloid cells to the tumor vasculature. We conclude that tumors use the catalytic activity of VAP-1 to recruit myeloid cells into tumors and to support tumor progression. Small-molecule VAP-1 inhibitors therefore might be a potential new tool for immunotherapy of tumors.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20154208
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8996
      1. Author :
        Cirstoiu-Hapca, A; Buchegger, F; Lange, N; Bossy, L; Gurny, R; Delie, F
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Journal of controlled release: official journal of the Controlled Release Society
      6. Products :
      7. Volume :
        144
      8. Issue :
        3
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Phytogenic; Bioware; Cell Line, Tumor; Drug Carriers; Female; Humans; Mice; Nanoparticles; Ovarian Neoplasms; Paclitaxel; Receptor, erbB-2; SKOV3-luc-D3 cells; Tissue Distribution; Xenograft Model Antitumor Assays
      12. Abstract :
        The benefit of polymeric immuno-nanoparticles (NPs-Tx-HER), consisting of paclitaxel (Tx)-loaded nanoparticles coated with anti-HER2 monoclonal antibodies (Herceptin, trastuzumab), in cancer treatment was assessed in a disseminated xenograft ovarian cancer model induced by intraperitoneal inoculation of SKOV-3 cells overexpressing HER2 antigens. The study was focused on the evaluation of therapeutic efficacy and biodistribution of NPs-Tx-HER compared to other Tx formulations. The therapeutic efficacy was determined by two methods: bioluminescence imaging and survival rate. The treatment regimen consisted in an initial dose of 20mg/kg Tx administered as 10mg/kg intravenously (IV) and 10mg/kg intraperitonealy (IP), followed by five alternative IP and IV injections of 10mg/kg Tx every 3 days. The bioluminescence study has clearly shown the superior anti-tumor activity of NPs-Tx-HER compared to free Tx. As a confirmation of these results, a significantly longer survival of mice was observed for NPs-Tx-HER treatment compared to free Tx, Tx-loaded nanoparticles coated with an irrelevant mAb (Mabthera, rituximab) or Herceptin alone, indicating the potential of immuno-nanoparticles in cancer treatment. The biodistribution pattern of Tx was assessed on healthy and tumor bearing mice after IV or IP administration. An equivalent biodistribution profile was observed in healthy mice for Tx encapsulated either in uncoated nanoparticles (NPs-Tx) or in NPs-Tx-HER. No significant difference in Tx biodistribution was observed after IV or IP injection, except for a lower accumulation in the lungs when NPs were administered by IP. Encapsulated Tx accumulated in the organs of the reticulo-endothelial system (RES) such as the liver and spleen, whereas free Tx had a non-specific distribution in all tested organs. Compared to free Tx, the single dose injection (IV or IP) of encapsulated Tx in mice bearing tumors induced a higher tumor accumulation. However, no difference in overall tumor accumulation between NPs-Tx-HER and NPs-Tx was observed. In conclusion, the encapsulation of Tx into NPs-Tx-HER immuno-nanoparticles resulted in an improved efficacy of drug in the treatment of disseminated ovarian cancer overexpressing HER2 receptors.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20219607
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9012
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