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      1. Author :
        Cheung, R.; Shen, F.; Phillips, J. H.; McGeachy, M. J.; Cua, D. J.; Heyworth, P. G.; Pierce, R. H.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        J Clin Invest
      6. Products :
      7. Volume :
        121
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IVIS, RediJect Inflammation Probe, chemiluminescence, XenoLight, Adaptor Proteins, Signal Transducing/metabolism; Animals; Cell Differentiation; Concanavalin A/toxicity; Dengue Hemorrhagic Fever/etiology; Disease Models, Animal; Disease Progression; Female; Humans; Immunity, Innate; Intracellular Signaling Peptides and Proteins/metabolism; Lectins, C-Type/deficiency/genetics/*immunology; Liver/metabolism/pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Immunological; Myeloid Cells/*immunology/pathology; Nitric Oxide/biosynthesis; Nitric Oxide Synthase Type II/metabolism; Nitric Oxide Synthase Type III/metabolism; Phosphatidylinositol 3-Kinases/metabolism; Protein-Tyrosine Kinases/metabolism; Proto-Oncogene Proteins c-akt/metabolism; Receptors, Cell Surface/deficiency/genetics/*immunology; Receptors, Immunologic/metabolism; Shock/*etiology/*immunology/metabolism/pathology; Signal Transduction; Systemic Inflammatory Response; Syndrome/etiology/immunology/metabolism/pathology; Tumor Necrosis Factor-alpha/biosynthesis
      12. Abstract :
        Systemic inflammatory response syndrome (SIRS) is a potentially lethal condition, as it can progress to shock, multi-organ failure, and death. It can be triggered by infection, tissue damage, or hemorrhage. The role of tissue injury in the progression from SIRS to shock is incompletely understood. Here, we show that treatment of mice with concanavalin A (ConA) to induce liver injury triggered a G-CSF-dependent hepatic infiltration of CD11b+Gr-1+Ly6G+Ly6C+ immature myeloid cells that expressed the orphan receptor myeloid DAP12-associated lectin-1 (MDL-1; also known as CLEC5A). Activation of MDL-1 using dengue virus or an agonist MDL-1-specific antibody in the ConA-treated mice resulted in shock. The MDL-1+ cells were pathogenic, and in vivo depletion of MDL-1+ cells provided protection. Triggering MDL-1 on these cells induced production of NO and TNF-alpha, which were found to be elevated in the serum of treated mice and required for MDL-1-induced shock. Surprisingly, MDL-1-induced NO and TNF-alpha production required eNOS but not iNOS. Activation of DAP12, DAP10, Syk, PI3K, and Akt was critical for MDL-1-induced shock. In addition, Akt physically interacted with and activated eNOS. Therefore, triggering of MDL-1 on immature myeloid cells and production of NO and TNF-alpha may play a critical role in the pathogenesis of shock. Targeting the MDL-1/Syk/PI3K/Akt/eNOS pathway represents a potential new therapeutic strategy to prevent the progression of SIRS to shock.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22005300
      14. Call Number :
        PKI @ kd.modi @ 2
      15. Serial :
        10421
      1. Author :
        Smith, Eric L; Schuchman, Edward H
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2008
      5. Publication :
        Molecular therapy: the journal of the American Society of Gene Therapy
      6. Products :
      7. Volume :
        16
      8. Issue :
        9
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Antineoplastic Agents; Autophagy; B16-F10-luc-G5 cells; Bioware; Cell Survival; Cells, Cultured; Ceramides; Cesium Radioisotopes; CHO Cells; Combined Modality Therapy; Cricetinae; Cricetulus; Endothelium, Vascular; Female; Gamma Rays; Gene Expression Regulation, Enzymologic; Gene Therapy; Humans; Melanoma, Experimental; Mice; Sphingomyelin Phosphodiesterase
      12. Abstract :
        Exposure of cells or animals to stress frequently induces acid sphingomyelinase (ASM)-mediated ceramide production that leads to cell death. Consistent with this, overexpression of ASM in subcutaneous B16-F10 mouse melanomas, in combination with irradiation, resulted in tumors that were up to 12-fold smaller than irradiated control melanomas. Similarly, when irradiated melanomas were pretreated with a single, peritumoral injection of recombinant ASM (rhASM), the tumors were up to threefold smaller. The in vivo effect of ASM was likely due to enhanced cell death of the tumor cells themselves, as well as the surrounding microvascular endothelial cells. In vitro, rhASM had little or no effect on the growth of tumor cells, even in combination with irradiation. However, when the culture media was acidified to mimic the acidic microenvironment of solid tumors, rhASM-mediated cell death was markedly enhanced when combined with irradiation. Microscopic analysis suggested that this was associated with an increase in autophagy. rhASM has been produced for the treatment of the lysosomal storage disorder, type B Niemann-Pick disease, and is currently being evaluated in a phase-1 clinical trial. Based on the data presented in this article, we propose that further investigation of this protein and gene as antineoplastic agents also is warranted.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/18628757
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8999
      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 :
        Palma, Joann P; Wang, Yi-Chun; Rodriguez, Luis E; Montgomery, Debra; Ellis, Paul A; Bukofzer, Gail; Niquette, Amanda; Liu, Xuesong; Shi, Yan; Lasko, Loren; Zhu, Gui-Dong; Penning, Thomas D; Giranda, Vincent L; Rosenberg, Saul H; Frost, David J; Donawho, Cherrie K
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Clinical cancer research: an official journal of the American Association for Cancer Research
      6. Products :
      7. Volume :
        15
      8. Issue :
        23
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Bioware; Dacarbazine; DNA Damage; DNA Modification Methylases; DNA Repair; DNA Repair Enzymes; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; MDA-MB-231-D3H2LN cells; Mice; Mice, SCID; Neoplasm Metastasis; Neoplasm Transplantation; Tumor Suppressor Proteins
      12. Abstract :
        PURPOSE ABT-888, currently in phase 2 trials, is a potent oral poly(ADP-ribose) polymerase inhibitor that enhances the activity of multiple DNA-damaging agents, including temozolomide (TMZ). We investigated ABT-888+TMZ combination therapy in multiple xenograft models representing various human tumors having different responses to TMZ. EXPERIMENTAL DESIGN ABT-888+TMZ efficacy in xenograft tumors implanted in subcutaneous, orthotopic, and metastatic sites was assessed by tumor burden, expression of poly(ADP-ribose) polymer, and O(6)-methylguanine methyltransferase (MGMT). RESULTS Varying levels of ABT-888+TMZ sensitivity were evident across a broad histologic spectrum of models (55-100% tumor growth inhibition) in B-cell lymphoma, small cell lung carcinoma, non-small cell lung carcinoma, pancreatic, ovarian, breast, and prostate xenografts, including numerous regressions. Combination efficacy in otherwise TMZ nonresponsive tumors suggests that TMZ resistance may be overcome by poly(ADP-ribose) polymerase inhibition. Profound ABT-888+TMZ efficacy was seen in experimental metastases models that acquired resistance to TMZ. Moreover, TMZ resistance was overcome in crossover treatments, indicating that combination therapy may overcome acquired TMZ resistance. Neither tumor MGMT, mismatch repair, nor poly(ADP-ribose) polymer correlated with the degree of sensitivity to ABT-888+TMZ. CONCLUSIONS Robust ABT-888+TMZ efficacy is observed across a spectrum of tumor types, including orthotopic and metastatic implantation. As many TMZ nonresponsive tumors proved sensitive to ABT-888+TMZ, this novel combination may broaden the clinical use of TMZ beyond melanoma and glioma. Although TMZ resistance may be influenced by MGMT, neither MGMT nor other mechanisms of TMZ resistance (mismatch repair) precluded sensitivity to ABT-888+TMZ. Underlying mechanisms of TMZ resistance in these models are not completely understood but likely involve mechanisms independent of MGMT.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19934293
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8954
      1. Author :
        Stangenberg L, Ellson C, Cortez-Retamozo V, Ortiz-Lopez A, Yuan H, Blois J, Smith RA, Yaffe MB, Weissleder R, Benoist C, Mathis D, Josephson L and Mahmood U
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Arthritis and Rheumatism
      6. Products :
      7. Volume :
        60
      8. Issue :
        8
      9. Page Numbers :
        N/A
      10. Research Area :
        Physiology
      11. Keywords :
        ProSense; AngioSense; arthritis; in vivo imaging
      12. Abstract :
        OBJECTIVE: To test a novel self-activating viridin (SAV) prodrug that slowly releases wortmannin, a potent phosphoinositide 3-kinase inhibitor, in a model of antibody-mediated inflammatory arthritis.

        METHODS: The SAV prodrug was administered to K/BxN mice or to C57BL/6 (B6) mice that had been injected with K/BxN serum. Ankle thickness was measured, and histologic changes were scored after a 10-day disease course (serum-transfer arthritis). Protease activity was measured by a near-infrared imaging approach using a cleavable cathepsin-selective probe. Further near-infrared imaging techniques were used to analyze early changes in vascular permeability after serum injection, as well as neutrophil-endothelial cell interactions. Neutrophil functions were assessed using an oxidative burst assay as well as a degranulation assay.

        RESULTS: SAV prevented ankle swelling in mice with serum-transfer arthritis in a dose-dependent manner. It also markedly reduced the extent of other features of arthritis, such as protease activity and histology scores for inflammation and joint erosion. Moreover, SAV was an effective therapeutic agent. The underlying mechanisms for the antiinflammatory activity were manifold. Endothelial permeability after serum injection was reduced, as was firm neutrophil attachment to endothelial cells. Endothelial cell activation by tumor necrosis factor alpha was impeded by SAV, as measured by the expression of vascular cell adhesion molecule. Crucial neutrophil functions, such as generation of reactive oxygen species and degranulation of protease-laden vesicles, were decreased by SAV administration.

        CONCLUSION: A novel SAV prodrug proved strongly antiinflammatory in a murine model of antibody-induced inflammatory arthritis. Its activity could be attributed, at least in part, to the inhibition of neutrophil and endothelial cell functions.
      13. URL :
        http://onlinelibrary.wiley.com/doi/10.1002/art.24704/abstract
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4528
      1. Author :
        Las Heras, F.; DaCosta, R. S.; Pritzker, K. P.; Haroon, N.; Netchev, G.; Tsui, H. W.; Chiu, B.; Erwin, W. M.; Tsui, F. W.; Inman, R. D.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Arthritis Res Ther
      6. Products :
      7. Volume :
        13
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        OsteoSense, Animals; Axis/chemistry/*metabolism/*pathology; *Calcification, Physiologic/genetics; Inflammation/genetics/metabolism/prevention & control; Mice; Mice, Transgenic; Molecular Imaging/*methods; Spondylitis, Ankylosing/diagnosis/*genetics/*metabolism; Time Factors
      12. Abstract :
        INTRODUCTION: The diagnosis of ankylosing spondylitis is made from a combination of clinical features and the presence of radiographic evidence that may be detected only after many years of inflammatory back pain. It is not uncommon to have a diagnosis confirmed 5 to 10 years after the initial onset of symptoms. Development of a more-sensitive molecular imaging technology to detect structural changes in the joints would lead to earlier diagnosis and quantitative tracking of ankylosis progression. Progressive ankylosis (ank/ank) mice have a loss of function in the Ank gene, which codes for a regulator of PPi transport. In this study, we used these ank/ank mutant mice to assess a noninvasive, quantitative measure of joint ankylosis with near-infrared (NIR) molecular imaging in vivo. METHODS: Three age groups (8, 12, and 18 weeks) of ank/ank (15 mice) and wild-type littermates (12 +/+ mice) were assessed histologically and radiographically. Before imaging, OsteoSense 750 (bisphosphonate pamidronate) was injected i.v. Whole-body images were analyzed by using the multispectral Maestro imaging system. RESULTS: OsteoSense 750 signals in the paw joints were higher in ank/ank mice in all three age groups compared with controls. In the spine, significantly higher OsteoSense 750 signals were detected early, in 8-week-old ank/ank mice compared with controls, although minimal radiographic differences were noted at this time point. The molecular imaging changes in the ank/ank spine (8 weeks) were supported by histologic changes, including calcium apatite crystals at the edge of the vertebral bodies and new syndesmophyte formation. CONCLUSIONS: Changes in joint pathology of ank/ank mice, as evaluated by histologic and radiographic means, are qualitative, but only semiquantitative. In contrast, molecular imaging provides a quantitative assessment. Ankylosis in ank/ank mice developed simultaneously in distal and axial joints, contrary to the previous notion that it is a centripetal process. NIR imaging might be feasible for early disease diagnosis and for monitoring disease progression in ankylosing spondylitis.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21992149
      14. Call Number :
        PKI @ kd.modi @ 3
      15. Serial :
        10471
      1. Author :
        Bethunaickan, R.; Berthier, C.C.; Ramanujam, M.; Sahu, R.; Zhang, W.; Sun, Y.; Bottinger, E.P.; Ivashkiv, L.; Kretzler, M.; Davidson, A.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Journal of Immunology (Baltimore, Md.: 1950)
      6. Products :
      7. Volume :
        N/A
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        In vivo; kidney; mice; MMPSense 680; ProSense 680
      12. Abstract :
        Renal infiltration with mononuclear cells is associated with poor prognosis in systemic lupus erythematosus. A renal macrophage/dendritic cell signature is associated with the onset of nephritis in NZB/W mice, and immune-modulating therapies can reverse this signature and the associated renal damage despite ongoing immune complex deposition. In nephritic NZB/W mice, renal F4/80(hi)/CD11c(int) macrophages are located throughout the interstitium, whereas F4/80(lo)/CD11c(hi) dendritic cells accumulate in perivascular lymphoid aggregates. We show here that F4/80(hi)/CD11c(int) renal macrophages have a Gr1(lo)/Ly6C(lo)/VLA4(lo)/MHCII(hi)/CD43(lo)/CD62L(lo) phenotype different from that described for inflammatory macrophages. At nephritis onset, F4/80(hi)/CD11c(int) cells upregulate cell surface CD11b, acquire cathepsin and matrix metalloproteinase activity, and accumulate large numbers of autophagocytic vacuoles; these changes reverse after the induction of remission. Latex bead labeling of peripheral blood Gr1(lo) monocytes indicates that these are the source of F4/80(hi)/CD11c(int) macrophages. CD11c(hi)/MHCII(lo) dendritic cells are found in the kidneys only after proteinuria onset, turnover rapidly, and disappear rapidly after remission induction. Gene expression profiling of the F4/80(hi)/CD11c(int) population displays increased expression of proinflammatory, regulatory, and tissue repair/degradation-associated genes at nephritis onset that reverses with remission induction. Our findings suggest that mononuclear phagocytes with an aberrant activation profile contribute to tissue damage in lupus nephritis by mediating both local inflammation and excessive tissue remodeling.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21411733
      14. Call Number :
        PKI @ user @ 8549
      15. Serial :
        4801
      1. Author :
        Georgel, Philippe; Crozat, Karine; Lauth, Xavier; Makrantonaki, Evgenia; Seltmann, Holger; Sovath, Sosathya; Hoebe, Kasper; Du, Xin; Rutschmann, Sophie; Jiang, Zhengfan; Bigby, Timothy; Nizet, Victor; Zouboulis, Christos C; Beutler, Bruce
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2005
      5. Publication :
        Infection and immunity
      6. Products :
      7. Volume :
        73
      8. Issue :
        8
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals; Anti-Bacterial Agents; Bioware; Chromosome Mapping; Eye Diseases; Fatty Acids, Monounsaturated; Likelihood Functions; Lod Score; Mice; Mice, Inbred C57BL; Oleic Acid; Receptors, Immunologic; Sequence Analysis, DNA; Skin; Staphylococcal Skin Infections; Stearoyl-CoA Desaturase; Streptococcus pyogenes; Time Factors; Toll-Like Receptor 2; Xen8.1, Xen20, Xen14
      12. Abstract :
        flake (flk), an N-ethyl-N-nitrosourea-induced recessive germ line mutation of C57BL/6 mice, impairs the clearance of skin infections by Streptococcus pyogenes and Staphylococcus aureus, gram-positive pathogens that elicit innate immune responses by activating Toll-like receptor 2 (TLR2). Positional cloning and sequencing revealed that flk is a novel allele of the stearoyl coenzyme A desaturase 1 gene (Scd1). flake homozygotes show reduced sebum production and are unable to synthesize the monounsaturated fatty acids (MUFA) palmitoleate (C(16:1)) and oleate (C(18:1)), both of which are bactericidal against gram-positive (but not gram-negative) organisms in vitro. However, intradermal MUFA administration to S. aureus-infected mice partially rescues the flake phenotype, which indicates that an additional component of the sebum may be required to improve bacterial clearance. In normal mice, transcription of Scd1-a gene with numerous NF-kappaB elements in its promoter--is strongly and specifically induced by TLR2 signaling. Similarly, the SCD1 gene is induced by TLR2 signaling in a human sebocyte cell line. These observations reveal the existence of a regulated, lipid-based antimicrobial effector pathway in mammals and suggest new approaches to the treatment or prevention of infections with gram-positive bacteria.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/16040962
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        9990
      1. Author :
        David G Kirsch; Daniela M Dinulescu; John B Miller; Jan Grimm; Philip M Santiago1; Nathan P Young; G Petur Nielsen; Bradley J Quade; Christopher J Chaber; Christian P Schultz; Osamu Takeuchi; Roderick T Bronson; Denise Crowley; Stanley J Korsmeyer; Sam S Yoon; Francis J Hornicek; Ralph Weissleder; Tyler Jacks
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2007
      5. Publication :
        Nature Medicine
      6. Products :
      7. Volume :
        13
      8. Issue :
        8
      9. Page Numbers :
        N/A
      10. Research Area :
        Cancer
      11. Keywords :
        sarcoma; imaging; apoptosis; metatasis; FMT
      12. Abstract :
        Soft tissue sarcomas are mesenchymal tumors that are fatal in approximately one-third of patients. To explore mechanisms of sarcoma pathogenesis, we have generated a mouse model of soft tissue sarcoma. Intramuscular delivery of an adenovirus expressing Cre recombinase in mice with conditional mutations in Kras and Trp53 was sufficient to initiate high-grade sarcomas with myofibroblastic differentiation. Like human sarcomas, these tumors show a predilection for lung rather than lymph node metastasis. Using this model, we showed that a prototype handheld imaging device can identify residual tumor during intraoperative molecular imaging. Deletion of the Ink4a-Arf locus (Cdkn2a), but not Bak1 and Bax, could substitute for mutation of Trp53 in this model. Deletion of Bak1 and Bax, however, was able to substitute for mutation of Trp53 in the development of sinonasal adenocarcinoma. Therefore, the intrinsic pathway of apoptosis seems sufficient to mediate p53 tumor suppression in an epithelial cancer, but not in this model of soft tissue sarcoma.
      13. URL :
        http://www.nature.com/nm/journal/v13/n8/abs/nm1602.html
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4506
      1. Author :
        Seo, G. M.; Rachakatla, R. S.; Balivada, S.; Pyle, M.; Shrestha, T. B.; Basel, M. T.; Myers, C.; Wang, H.; Tamura, M.; Bossmann, S. H.; Troyer, D. L.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Mol Biol Rep
      6. Products :
      7. Volume :
        39
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals, B16-F10-luc2, B16F10-luc2
      12. Abstract :
        Gene-directed enzyme prodrug therapy (GDEPT) has been investigated as a means of cancer treatment without affecting normal tissues. This system is based on the delivery of a suicide gene, a gene encoding an enzyme which is able to convert its substrate from non-toxic prodrug to cytotoxin. In this experiment, we have developed a targeted suicide gene therapeutic system that is completely contained within tumor-tropic cells and have tested this system for melanoma therapy in a preclinical model. First, we established double stable RAW264.7 monocyte/macrophage-like cells (Mo/Ma) containing a Tet-On(R) Advanced system for intracellular carboxylesterase (InCE) expression. Second, we loaded a prodrug into the delivery cells, double stable Mo/Ma. Third, we activated the enzyme system to convert the prodrug, irinotecan, to the cytotoxin, SN-38. Our double stable Mo/Ma homed to the lung melanomas after 1 day and successfully delivered the prodrug-activating enzyme/prodrug package to the tumors. We observed that our system significantly reduced tumor weights and numbers as targeted tumor therapy after activation of the InCE. Therefore, we propose that this system may be a useful targeted melanoma therapy system for pulmonary metastatic tumors with minimal side effects, particularly if it is combined with other treatments.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21567204
      14. Call Number :
        PKI @ kd.modi @ 6
      15. Serial :
        10351
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