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      1. Author :
        Phillips, W. T.; Goins, B.; Bao, A.; Vargas, D.; Guttierez, J. E.; Trevino, A.; Miller, J. R.; Henry, J.; Zuniga, R.; Vecil, G.; Brenner, A. J.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Neuro Oncol
      6. Products :
      7. Volume :
        14
      8. Issue :
        N/A
      9. Page Numbers :
        416-25
      10. Research Area :
        N/A
      11. Keywords :
        U-87 MG-luc2, U-87-MG-luc2, Glioma, Bioware, IVIS, Animals; Brachytherapy/*methods; Brain Neoplasms/pathology/*radiotherapy; Convection; Glioblastoma/pathology/*radiotherapy; Glioma/pathology/*radiotherapy; Liposomes; Nanoparticles/therapeutic use; Radioisotopes/*therapeutic use; Rats; Rhenium/*therapeutic use; Tumor Burden; Xenograft Model Antitumor Assays
      12. Abstract :
        Although external beam radiation is an essential component to the current standard treatment of primary brain tumors, its application is limited by toxicity at doses more than 80 Gy. Recent studies have suggested that brachytherapy with liposomally encapsulated radionuclides may be of benefit, and we have reported methods to markedly increase the specific activity of rhenium-186 ((186)Re)-liposomes. To better characterize the potential delivery, toxicity, and efficacy of the highly specific activity of (186)Re-liposomes, we evaluated their intracranial application by convection-enhanced delivery in an orthotopic U87 glioma rat model. After establishing an optimal volume of 25 microL, we observed focal activity confined to the site of injection over a 96-hour period. Doses of up to 1850 Gy were administered without overt clinical or microscopic evidence of toxicity. Animals treated with (186)Re-liposomes had a median survival of 126 days (95% confidence interval [CI], 78.4-173 days), compared with 49 days (95% CI, 44-53 days) for controls. Log-rank analysis between these 2 groups was highly significant (P = .0013) and was even higher when 100 Gy was used as a cutoff (P < .0001). Noninvasive luciferase imaging as a surrogate for tumor volume showed a statistically significant separation in bioluminescence by 11 days after 100 Gy or less treatment between the experimental group and the control animals (chi(2)[1, N= 19] = 4.8; P = .029). MRI also supported this difference in tumor size. Duplication of tumor volume differences and survival benefit was possible in a more invasive U251 orthotopic model, with clear separation in bioluminescence at 6 days after treatment (chi(2)[1, N= 9] = 4.7; P = .029); median survival in treated animals was not reached at 120 days because lack of mortality, and log-rank analysis of survival was highly significant (P = .0057). Analysis of tumors by histology revealed minimal areas of necrosis and gliosis. These results support the potential efficacy of the highly specific activity of brachytherapy by (186)Re-liposomes convection-enhanced delivery in glioma.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22427110
      14. Call Number :
        PKI @ kd.modi @ 2
      15. Serial :
        10500
      1. Author :
        Wen, D.; Qing, L.; Harrison, G.; Golub, E.; Akintoye, S. O.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Oral Dis
      6. Products :
      7. Volume :
        17
      8. Issue :
        N/A
      9. Page Numbers :
        427-32
      10. Research Area :
        N/A
      11. Keywords :
        OsteoSense, Maestro, Animals; Bone Density Conservation Agents/administration & dosage/*pharmacokinetics; Bone and Bones/*metabolism; Calcium/metabolism; Chelating Agents; Decalcification Technique; Diphosphonates/administration & dosage/*pharmacokinetics; Durapatite/metabolism; Edetic Acid; Female; Femur/metabolism; Fibula/metabolism; Fluorescent Dyes/diagnostic use; Fluorometry; Humerus/metabolism; Injections, Intravenous; Mandible/metabolism; Models, Animal; Radius/metabolism; Rats; Rats, Nude; Spectrophotometry, Atomic; Tibia/metabolism; Tissue Distribution; Ulna/metabolism
      12. Abstract :
        OBJECTIVES: Bisphosphonates commonly used to treat osteoporosis, Paget's disease, multiple myeloma, hypercalcemia of malignancy and osteolytic lesions of cancer metastasis have been associated with bisphosphonate-associated jaw osteonecrosis (BJON). The underlying pathogenesis of BJON is unclear, but disproportionate bisphosphonate concentration in the jaw has been proposed as one potential etiological factor. This study tested the hypothesis that skeletal biodistribution of intravenous bisphosphonate is anatomic site-dependent in a rat model system. MATERIALS AND METHODS: Fluorescently labeled pamidronate was injected intravenously in athymic rats of equal weights followed by in vivo whole body fluorimetry, ex vivo optical imaging of oral, axial, and appendicular bones and ethylenediaminetetraacetic acid bone decalcification to assess hydroxyapatite-bound bisphosphonate. RESULTS: Bisphosphonate uptake and bisphosphonate released per unit calcium were similar in oral and appendicular bones but lower than those in axial bones. Hydroxyapatite-bound bisphosphonate liberated by sequential acid decalcification was the highest in oral, relative to axial and appendicular bones (P < 0.05). CONCLUSIONS: This study demonstrates regional differences in uptake and release of bisphosphonate from oral, axial, and appendicular bones of immune deficient rats.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21122034
      14. Call Number :
        PKI @ kd.modi @ 11
      15. Serial :
        10467
      1. Author :
        Agarwal, A.; Mackey, M. A.; El-Sayed, M. A.; Bellamkonda, R. V.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        ACS Nano
      6. Products :
      7. Volume :
        5
      8. Issue :
        N/A
      9. Page Numbers :
        4919-26
      10. Research Area :
        N/A
      11. Keywords :
        Annexin Vivo, Annexin-Vivo, IVIS, Animals; Antineoplastic Agents/*administration & dosage; Apoptosis; Cell Line, Tumor; Doxorubicin/*administration & dosage; Drug Carriers; Drug Delivery Systems; Female; Glioblastoma/drug therapy; Gold/chemistry; Humans; Liposomes/*chemistry; Metal Nanoparticles/chemistry; Mice; Mice, Nude; Nanostructures/chemistry; Neoplasms/*drug therapy; Polyethylene Glycols/chemistry
      12. Abstract :
        Delivery of chemotherapeutic agents after encapsulation in nanocarriers such as liposomes diminishes side-effects, as PEGylated nanocarrier pharmacokinetics decrease dosing to healthy tissues and accumulate in tumors due to the enhanced permeability and retention effect. Once in the tumor, however, dosing of the chemotherapeutic to tumor cells is limited potentially by the rate of release from the carriers and the size-constrained, poor diffusivity of nanocarriers in tumor interstitium. Here, we report the design and fabrication of a thermosensitive liposomal nanocarrier that maintains its encapsulation stability with a high concentration of doxorubicin payload, thereby minimizing “leak” and attendant toxicity. When used synergistically with PEGylated gold nanorods and near-infrared stimulation, remote triggered release of doxorubicin from thermosensitive liposomes was achieved in a mouse tumor model of human glioblastoma (U87), resulting in a significant increase in efficacy when compared to nontriggered or nonthermosensitive PEGylated liposomes. This enhancement in efficacy is attributed to increase in tumor-site apoptosis, as was evident from noninvasive apoptosis imaging using Annexin-Vivo 750 probe. This strategy affords remotely triggered control of tumor dosing of nanocarrier-encapsulated doxorubicin without sacrificing the ability to differentially dose drugs to tumors via the enhanced permeation and retention effect.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21591812
      14. Call Number :
        PKI @ kd.modi @ 1
      15. Serial :
        10430
      1. Author :
        Subbarayan, P. R.; Sarkar, M.; Nagaraja Rao, S.; Philip, S.; Kumar, P.; Altman, N.; Reis, I.; Ahmed, M.; Ardalan, B.; Lokeshwar, B. L.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        J Ethnopharmacol
      6. Products :
      7. Volume :
        142
      8. Issue :
        N/A
      9. Page Numbers :
        523-30
      10. Research Area :
        N/A
      11. Keywords :
        BxPC-3, BxPC-3-luc2, IVIS, Achyranthes; Animals; Antineoplastic Agents, Phytogenic/pharmacology/*therapeutic use; Apoptosis/*drug effects; Caspase 3/genetics/metabolism; Gene Expression/drug effects; Humans; Injections, Intraperitoneal; Medicine, Ayurvedic; Mice; Mice, Nude; Pancreatic Neoplasms/*drug therapy/genetics/metabolism; Phosphorylation; *Phytotherapy; Plant Extracts/pharmacology/*therapeutic use; Plant Leaves; Proto-Oncogene Proteins c-akt/metabolism; RNA, Messenger/metabolism; Xenograft Model Antitumor Assays
      12. Abstract :
        ETHNOPHARMACOLOGICAL RELEVANCE: Achyranthes aspera (Family Amaranthacea) is used for cancer therapy by ayurvedic medical practitioners in India. However, due to the non formal nature of its use, there are no systematic studies validating its medicinal properties. Thus, it's utility as an anti cancer agent remains anecdotal. Earlier, we demonstrated A. aspera to exhibit time and dose-dependent preferential cytotoxicity to cultured human pancreatic cancer cells. In this report we validate in vivo anti tumor properties of A. aspera. MATERIALS AND METHODS: The in vivo anti tumor activity of leaf extract (LE) was tested by intraperitoneal (IP) injections into athymic mice harboring human pancreatic tumor subcutaneous xenograft. Toxicity was monitored by recording changes in behavioral, histological, hematological and body weight parameters. RESULTS: Dosing LE to athymic mice by I.P. injection for 32 days showed no adverse reactions in treated mice. Compared to the control set, IP administration of LE to tumor bearing mice significantly reduced both tumor weight and volume. Gene expression analysis using Real time PCR methods revealed that LE significantly induced caspase-3 mRNA (p<0.001) and suppressed expression of the pro survival kinase Akt-1 (p<0.05). TUNEL assay and immunohistochemistry confirmed apoptosis induction by activation of caspase-3 and inhibiting Akt phosphorylation in treated sets. These results are in agreement with RT PCR data. CONCLUSION: Taken together, these data suggest A. aspera to have potent anti cancer property.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22640722
      14. Call Number :
        PKI @ kd.modi @ 1
      15. Serial :
        10484
      1. Author :
        Welti, J. C.; Powles, T.; Foo, S.; Gourlaouen, M.; Preece, N.; Foster, J.; Frentzas, S.; Bird, D.; Sharpe, K.; van Weverwijk, A.; Robertson, D.; Soffe, J.; Erler, J. T.; Pili, R.; Springer, C. J.; Mather, S. J.; Reynolds, A. R.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Angiogenesis
      6. Products :
      7. Volume :
        15
      8. Issue :
        N/A
      9. Page Numbers :
        623-41
      10. Research Area :
        N/A
      11. Keywords :
        4T1-luc2, 4T1, Bioware, IVIS
      12. Abstract :
        Sunitinib is a potent and clinically approved tyrosine kinase inhibitor that can suppress tumour growth by inhibiting angiogenesis. However, conflicting data exist regarding the effects of this drug on the growth of metastases in preclinical models. Here we use 4T1 and RENCA tumour cells, which both form lung metastases in Balb/c mice, to re-address the effects of sunitinib on the progression of metastatic disease in mice. We show that treatment of mice with sunitinib prior to intravenous injection of tumour cells can promote the seeding and growth of 4T1 lung metastases, but not RENCA lung metastases, showing that this effect is cell line dependent. However, increased metastasis occurred only upon administration of a very high sunitinib dose, but not when lower, clinically relevant doses were used. Mechanistically, high dose sunitinib led to a pericyte depletion effect in the lung vasculature that correlated with increased seeding of metastasis. By administering sunitinib to mice after intravenous injection of tumour cells, we demonstrate that while sunitinib does not inhibit the growth of 4T1 lung tumour nodules, it does block the growth of RENCA lung tumour nodules. This contrasting response was correlated with increased myeloid cell recruitment and persistent vascularisation in 4T1 tumours, whereas RENCA tumours recruited less myeloid cells and were more profoundly devascularised upon sunitinib treatment. Finally, we show that progression of 4T1 tumours in sunitinib treated mice results in increased hypoxia and increased glucose metabolism in these tumours and that this is associated with a poor outcome. Taken together, these data suggest that the effects of sunitinib on tumour progression are dose-dependent and tumour model-dependent. These findings have relevance for understanding how anti-angiogenic agents may influence disease progression when used in the adjuvant or metastatic setting in cancer patients.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22843200
      14. Call Number :
        PKI @ kd.modi @ 10
      15. Serial :
        10504
      1. Author :
        Srivastava, Amit; Henneke, Philipp; Visintin, Alberto; Morse, Sarah C; Martin, Victoria; Watkins, Claire; Paton, James C; Wessels, Michael R; Golenbock, Douglas T; Malley, Richard
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2005
      5. Publication :
        Infection and immunity
      6. Products :
      7. Volume :
        73
      8. Issue :
        10
      9. Page Numbers :
        6479-6487
      10. Research Area :
        N/A
      11. Keywords :
        Amino Acid Chloromethyl Ketones; Animals; Apoptosis; Bacterial Proteins; Caspases; Lipopolysaccharides; Macrophages; Mice; Mice, Inbred Strains; Nasopharynx; Pneumococcal Infections; Streptococcus pneumoniae; Streptolysins; Xen10
      12. Abstract :
        Pneumolysin, the cholesterol-dependent cytolysin of Streptococcus pneumoniae, induces inflammatory and apoptotic events in mammalian cells. Toll-like receptor 4 (TLR4) confers resistance to pneumococcal infection via its interaction with pneumolysin, but the underlying mechanisms remain to be identified. In the present study, we found that pneumolysin-induced apoptosis is also mediated by TLR4 and confers protection against invasive disease. The interaction between TLR4 and pneumolysin is direct and specific; ligand-binding studies demonstrated that pneumolysin binds to TLR4 but not to TLR2. Involvement of TLR4 in pneumolysin-induced apoptosis was demonstrated in several complementary experiments. First, macrophages from wild-type mice were significantly more prone to pneumolysin-induced apoptosis than cells from TLR4-defective mice. In gain-of-function experiments, we found that epithelial cells expressing TLR4 and stimulated with pneumolysin were more likely to undergo apoptosis than cells expressing TLR2. A specific TLR4 antagonist, B1287, reduced pneumolysin-mediated apoptosis in wild-type cells. This apoptotic response was also partially caspase dependent as preincubation of cells with the pan-caspase inhibitor zVAD-fmk reduced pneumolysin-induced apoptosis. Finally, in a mouse model of pneumococcal infection, pneumolysin-producing pneumococci elicited significantly more upper respiratory tract cell apoptosis in wild-type mice than in TLR4-defective mice, and blocking apoptosis by administration of zVAD-fmk to wild-type mice resulted in a significant increase in mortality following nasopharyngeal pneumococcal exposure. Overall, our results strongly suggest that protection against pneumococcal disease is dependent on the TLR4-mediated enhancement of pneumolysin-induced apoptosis.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/16177320
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        10001
      1. Author :
        Domanska, U. M.; Timmer-Bosscha, H.; Nagengast, W. B.; Oude Munnink, T. H.; Kruizinga, R. C.; Ananias, H. J.; Kliphuis, N. M.; Huls, G.; De Vries, E. G.; de Jong, I. J.; Walenkamp, A. M.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Neoplasia
      6. Products :
      7. Volume :
        14
      8. Issue :
        N/A
      9. Page Numbers :
        709-18
      10. Research Area :
        N/A
      11. Keywords :
        PC-3-luc2, Prostate Cancer, Bioware, IVIS
      12. Abstract :
        Several in vitro and in vivo models have revealed the key role of CXCR4/CXCL12 axis in tumor-stroma interactions. Stromal cells present in the tumor microenvironment express high levels of CXCL12 protein, directly stimulating proliferation and migration of CXCR4-expressing cancer cells. This specific prosurvival influence of stromal cells on tumor cells is thought to protect them from cytotoxic chemotherapy and is postulated as a possible explanation for the minimal residual disease in hematological and solid cancers. Therefore, CXCR4/CXCL12 signaling is an attractive therapeutic target in cancer, as proven in preclinical leukemia mouse models, where CXCR4 inhibition sensitized cancer cells to conventional chemotherapy. This study investigates whether inhibition of CXCR4 with the specific inhibitor AMD3100 sensitizes human prostate cancer cells to docetaxel. We showed that both mouse and human stromal cell lines have a protective effect on PC3-luc cells by promoting their survival after chemotherapy. Furthermore, we demonstrated that AMD3100 sensitizes PC3-luc cells to docetaxel. In a subcutaneous xenograft mouse model of human prostate carcinoma, we showed that a combination of docetaxel and AMD3100 exerts increased antitumor effect compared with docetaxel alone. We concluded that CXCR4 inhibition chemosensitizes prostate cancer cells, both in vitro and in vivo. To explore the relevance of these findings, we analyzed CXCR4 expression levels in human prostate cancer samples. We found that cancer cells present in bone metastatic lesions express higher CXCR4 levels relative to the cells present in primary tumors and lymph node metastatic lesions. These findings underscore the potential of CXCR4 inhibitors as chemosensitizing agents.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22952424
      14. Call Number :
        PKI @ kd.modi @ 1
      15. Serial :
        10507
      1. Author :
        Pesnel, S.; Pillon, A.; Creancier, L.; Lerondel, S.; Le Pape, A.; Recher, C.; Demur, C.; Guilbaud, N.; Kruczynski, A.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        PLoS One
      6. Products :
      7. Volume :
        7
      8. Issue :
        N/A
      9. Page Numbers :
        e30690
      10. Research Area :
        N/A
      11. Keywords :
        HCT-116-luc2, HCT116-luc2, IVIS, Animals; Antibodies, Monoclonal/administration & dosage/*immunology; Antigens, CD45/metabolism; Cell Line, Tumor; Cell Transformation, Neoplastic/pathology; Disease Models, Animal; Flow Cytometry; Fluorescent Dyes/*metabolism; Humans; Imaging, Three-Dimensional/*methods; Injections, Intravenous; Leukemia/*diagnosis/*pathology; Leukemia, Myeloid, Acute/pathology; Longevity; Luminescent Measurements; Mice; Mice, SCID; Reproducibility of Results; Spectroscopy, Near-Infrared/*methods
      12. Abstract :
        BACKGROUND: The assessment of anticancer agents to treat leukemia needs to have animal models closer to the human pathology such as implantation in immunodeficient mice of leukemic cells from patient samples. A sensitive and early detection of tumor cells in these orthotopic models is a prerequisite for monitoring engraftment of leukemic cells and their dissemination in mice. Therefore, we developed a fluorescent antibody based strategy to detect leukemic foci in mice bearing patient-derived leukemic cells using fluorescence reflectance imaging (FRI) to determine when to start treatments with novel antitumor agents. METHODS: Two mAbs against the CD44 human myeloid marker or the CD45 human leukocyte marker were labeled with Alexa Fluor 750 and administered to leukemia-bearing mice after having verified the immunoreactivity in vitro. Bioluminescent leukemic cells (HL60-Luc) were used to compare the colocalization of the fluorescent mAb with these cells. The impact of the labeled antibodies on disease progression was further determined. Finally, the fluorescent hCD45 mAb was tested in mice engrafted with human leukemic cells. RESULTS: The probe labeling did not modify the immunoreactivity of the mAbs. There was a satisfactory correlation between bioluminescence imaging (BLI) and FRI and low doses of mAb were sufficient to detect leukemic foci. However, anti-hCD44 mAb had a strong impact on the tumor proliferation contrary to anti-hCD45 mAb. The use of anti-hCD45 mAb allowed the detection of leukemic patient cells engrafted onto NOD/SCID mice. CONCLUSIONS: A mAb labeled with a near infrared fluorochrome is useful to detect leukemic foci in disseminated models provided that its potential impact on tumor proliferation has been thoroughly documented.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22303450
      14. Call Number :
        PKI @ kd.modi @ 4
      15. Serial :
        10503
      1. Author :
        Zhang, J.; Preda, D. V.; Vasquez, K. O.; Morin, J.; Delaney, J.; Bao, B.; Percival, M. D.; Xu, D.; McKay, D.; Klimas, M.; Bednar, B.; Sur, C.; Gao, D. Z.; Madden, K.; Yared, W.; Rajopadhye, M.; Peterson, J. D.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Am J Physiol Renal Physiol
      6. Products :
      7. Volume :
        303
      8. Issue :
        N/A
      9. Page Numbers :
        F593-603
      10. Research Area :
        N/A
      11. Keywords :
        ReninSense 680 FAST, FMT, Animal Feed/analysis; Animals; Cathepsin D; Cathepsin G; Female; Fluorescent Dyes/*pharmacology; Humans; Mice; Mice, Inbred C57BL; Peptides/*pharmacology; Peptidyl-Dipeptidase A/metabolism; Rats; Renin/*blood/*metabolism; Renin-Angiotensin System/physiology; Sensitivity and Specificity; Sodium, Dietary
      12. Abstract :
        The renin-angiotensin system (RAS) is well studied for its regulation of blood pressure and fluid homeostasis, as well as for increased activity associated with a variety of diseases and conditions, including cardiovascular disease, diabetes, and kidney disease. The enzyme renin cleaves angiotensinogen to form angiotensin I (ANG I), which is further cleaved by angiotensin-converting enzyme to produce ANG II. Although ANG II is the main effector molecule of the RAS, renin is the rate-limiting enzyme, thus playing a pivotal role in regulating RAS activity in hypertension and organ injury processes. Our objective was to develop a near-infrared fluorescent (NIRF) renin-imaging agent for noninvasive in vivo detection of renin activity as a measure of tissue RAS and in vitro plasma renin activity. We synthesized a renin-activatable agent, ReninSense 680 FAST (ReninSense), using a NIRF-quenched substrate derived from angiotensinogen that is cleaved specifically by purified mouse and rat renin enzymes to generate a fluorescent signal. This agent was assessed in vitro, in vivo, and ex vivo to detect and quantify increases in plasma and kidney renin activity in sodium-sensitive inbred C57BL/6 mice maintained on a low dietary sodium and diuretic regimen. Noninvasive in vivo fluorescence molecular tomographic imaging of the ReninSense signal in the kidney detected increased renin activity in the kidneys of hyperreninemic C57BL/6 mice. The agent also effectively detected renin activity in ex vivo kidneys, kidney tissue sections, and plasma samples. This approach could provide a new tool for assessing disorders linked to altered tissue and plasma renin activity and to monitor the efficacy of therapeutic treatments.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22674025
      14. Call Number :
        PKI @ kd.modi @ 1
      15. Serial :
        10572