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排序方式: 共有701条查询结果,搜索用时 46 毫秒
81.
Lebedeva IV Emdad L Su ZZ Gupta P Sauane M Sarkar D Staudt MR Liu SJ Taher MM Xiao R Barral P Lee SG Wang D Vozhilla N Park ES Chatman L Boukerche H Ramesh R Inoue S Chada S Li R De Pass AL Mahasreshti PJ Dmitriev IP Curiel DT Yacoub A Grant S Dent P Senzer N Nemunaitis JJ Fisher PB 《International journal of oncology》2007,31(5):985-1007
Subtraction hybridization applied to a 'differentiation therapy' model of cancer employing human melanoma cells resulted in the cloning of melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24). Initial studies confirm an inverse correlation between mda-7 expression and melanoma development and progression. Forced expression of mda-7 by means of a plasmid or via a replication incompetent adenovirus (Ad.mda-7) promotes growth suppression and induces apoptosis in a broad array of human cancers. In contrast, mda-7 does not induce growth suppressive or toxic effects in normal cells. Based on structure (containing an IL-10 signature motif), secretion by cells (including subsets of T-cells) and location on chromosome 1q (in an area containing IL-10-family genes), mda-7 has now been renamed mda-7/IL-24. Studies by several laboratories have uncovered many of mda-7/IL-24's unique properties, including cancer-specific apoptosis-induction, cell cycle regulation, an ability to inhibit angiogenesis, potent 'bystander antitumor activity' and a capacity to enhance the sensitivity of tumor cells to radiation, chemotherapy and monoclonal antibody therapy. Moreover, based on its profound cancer tropism, substantiated by in vivo human xenograft studies in nude mice, mda-7/IL-24 (administered as Ad.mda-7) was evaluated in a phase I clinical trial in patients with melanomas and solid cancers. These studies document that mda-7/IL-24 is well tolerated and demonstrates evidence of significant clinical activity. In these contexts, mda-7/IL-24 represents a unique cytokine gene with potential for therapy of human cancers. The present review focuses on three unique properties of mda-7/IL-24, namely its potent 'bystander antitumor activity', ability to sensitize tumor cells to radiation, and its antiangiogenesis properties. Additionally, an overview of the phase I clinical trial is provided. These studies affirm that mda-7/IL-24 has promise for the management of diverse cancers. 相似文献
82.
Yacoub A Hawkins W Hanna D Young H Park MA Grant M Roberts JD Curiel DT Fisher PB Valerie K Grant S Hagan MP Dent P 《Molecular pharmacology》2007,71(1):259-275
The impact of human chorionic gonadotropin (hCG) on prostate carcinoma viability was investigated. Treatment of LNCaP and PC-3 cells with hCG modestly reduced cell viability within 96 h. Treatment of cells with hCG followed by exposure to ionizing radiation enhanced radiosensitivity. Exposure of LNCaP cells to hCG promoted activation of epidermal growth factor receptor (ERBB1) via a Galpha(i)-, mitogen-activated protein kinase kinase (MEK)1/2-, and metalloprotease-dependent paracrine mechanism, effects that were further enhanced after radiation exposure, and that were causal in prolonged intense activation of poly(ADP-ribose) polymerase (PARP). Inhibition of ERBB1, MEK1, or PARP1 function suppressed the radiosensitizing properties of hCG. Radiosensitization was also, in part, dependent upon c-Jun NH2-terminal kinase 1/2 signaling. PARP1-dependent radiosensitization was suppressed by a pan-caspase inhibitor and by knockdown of apoptosis-inducing factor expression. Inhibition of phosphatidylinositol 3-kinase, expression of dominant-negative AKT, or treatment with the HMG CoA reductase inhibitor lovastatin suppressed AKT phosphorylation and enhanced the cytotoxic effects of hCG. The enhancing effect of lovastatin was reproduced by incubation with a geranylgeranyl transferase inhibitor and blocked by coexposure to geranylgeranyl pyrophosphate. Treatment with hCG and lovastatin decreased expression of BCL-(XL) and XIAP, and increased expression of IkappaB. The cytotoxic effects of hCG were enhanced by expression of dominant-negative IkappaB, and they were abolished by coexpression of activated AKT. Expression of activated AKT maintained BCL-(XL) levels in cells expressing dominant-negative IkappaB. The promotion of hCG lethality by lovastatin was abolished by overexpression of BCL-(XL), and was dependent upon activation of caspase-9. Thus, hCG, in combination with radiation and lovastatin, may represent a novel approach to kill prostate cancer cells. 相似文献
83.
84.
Use of cells as therapeutic carriers has increased in the past few years and has developed as a distinct concept and delivery method. Cell-based vehicles are particularly attractive for delivery of biotherapeutic agents that are difficult to synthesize, have reduced half-lives, limited tissue penetrance or are rapidly inactivated upon direct in vivo introduction. Initial studies using cell-based approaches served to identify some of the key factors for the success of this type of therapeutic delivery. These factors include the efficiency of cell loading with a therapeutic payload, the means of cell loading and the nature of therapeutics that cells can carry. However, one important aspect of cell-based delivery yet to be fully investigated is the process of actual delivery of the cell payload in vivo. In this regard, the potential ability of cell carriers to provide site-specific or targeted delivery of therapeutics deserves special attention. The present review focuses on a variety of targeting approaches that may be utilized to improve cell-based therapeutic delivery strategies. The different aspects of targeting that can be applied to cell vehicles will be discussed, including physical methods for directing cell distribution, intrinsic cell-mediated homing mechanisms and the feasibility of engineering cells with novel targeting mechanisms. Development of cell targeting strategies will further advance cell vehicle applications, broaden the applicability of this delivery approach and potentiate therapeutic outcomes. 相似文献
85.
Caspase-, cathepsin-, and PERK-dependent regulation of MDA-7/IL-24-induced cell killing in primary human glioma cells 总被引:1,自引:0,他引:1
Yacoub A Park MA Gupta P Rahmani M Zhang G Hamed H Hanna D Sarkar D Lebedeva IV Emdad L Sauane M Vozhilla N Spiegel S Koumenis C Graf M Curiel DT Grant S Fisher PB Dent P 《Molecular cancer therapeutics》2008,7(2):297-313
Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) is a novel cytokine displaying selective apoptosis-inducing activity in transformed cells without harming normal cells. The present studies focused on defining the mechanism(s) by which a GST-MDA-7 fusion protein inhibits cell survival of primary human glioma cells in vitro. GST-MDA-7 killed glioma cells with diverse genetic characteristics that correlated with inactivation of ERK1/2 and activation of JNK1-3. Activation of JNK1-3 was dependent on protein kinase R-like endoplasmic reticulum kinase (PERK), and GST-MDA-7 lethality was suppressed in PERK-/- cells. JNK1-3 signaling activated BAX, whereas inhibition of JNK1-3, deletion of BAX, or expression of dominant-negative caspase-9 suppressed lethality. GST-MDA-7 also promoted a PERK-, JNK-, and cathepsin B-dependent cleavage of BID; loss of BID function promoted survival. GST-MDA-7 suppressed BAD and BIM phosphorylation and heat shock protein 70 (HSP70) expression. GST-MDA-7 caused PERK-dependent vacuolization of LC3-expressing endosomes whose formation was suppressed by incubation with 3-methyladenine, expression of HSP70 or BiP/GRP78, or knockdown of ATG5 or Beclin-1 expression but not by inhibition of the JNK1-3 pathway. Knockdown of ATG5 or Beclin-1 expression or overexpression of HSP70 reduced GST-MDA-7 lethality. Our data show that GST-MDA-7 induces an endoplasmic reticulum stress response that is causal in the activation of multiple proapoptotic pathways, which converge on the mitochondrion and highlight the complexity of signaling pathways altered by mda-7/IL-24 in glioma cells that ultimately culminate in decreased tumor cell survival. 相似文献
86.
87.
Development of a therapeutic adenoviral vector for cholangiocarcinoma combining tumor-restricted gene expression and infectivity enhancement 总被引:2,自引:0,他引:2
Peter Nagi M.D. Selwyn M. Vickers M.D. Julia Davydova M.D. Ph.D. Yasuo Adachi M.D. Ph.D. Koichi Takayama M.D. Ph.D. Shannon Barker Victor Krasnykh Ph.D. David T. Curiel M.D. Masato Yamamoto M.D. Ph.D. 《Journal of gastrointestinal surgery》2003,7(3):364-371
Cholangiocarcinoma is an invasive malignancy that is most often unresectable upon diagnosis and unresponsive to chemotherapy
and radiation. While adenoviral gene therapy has shown promise in treating many tumors, systemic toxicity and low tumor transduction
efficiency have hampered its application in many gastrointestinal cancers. To overcome these difficulties, we have constructed
an adenoviral vector utilizing a tumor-specific promoter (TSP) for selective transgene expression and a vector with an RGD-motif
in the fiber-knob region for infectivity enhancement. In seeking a TSP for cholangiocarcinoma, Secretory Leukoprotease Inhibitor,
Midkine, Gastrin Releasing Peptide, VEGF, Cox-2M, and Cox-2L promoters were configures in adenoviral vectors, and evaluated
in cholangiocarcinoma cells lines (Oz and SkChA-1). Luciferase assays demonstrated that Cox-2 promoters (M and L) showed the
highest promoter activity, with Cox-2M appearing slightly stronger than Cox-2L. Infectivity enhanced vectors with RGD-motif
in the fiber-knob region were also constructed with the luciferase transgene driven by a CMV control and the Cox-2M and Cox-2L
promoters. Subsequent luciferase assays comparing the unmodified vectors to the RGD-modified versions demonstrated higher
levels of luciferase activity than the RGD-infected cells. This paradigm was then applied to a therapeutic HSV-TK/GCV model
by constructing RGD-enhanced HSV-TK vectors driven by Cox-2M and Cox-2L promoters. In vitro cytocidal effect analysis confirmed
that the RGD-modified, cox-2 (M and L) driven vectors showed a stronger cytocidal effect upon gancyclovir administration than
the vectors with wild-type fiber. The Cox-2 promoter demonstrates a favorable selectivity profile for cholangiocarcinoma,
and RGD-modification further enhances transduction efficiency. This combination has potential to overcome the obstacles to
clinical application of adenoviral gene therapy in cholangiocarcinoma.
Presented at the Forty-Third Annual Meeting of The Society for Surgery of The Alimentary Tract, San Francisco, California,
May 19–22, 2002 (oral presentation). 相似文献
88.
Splenic lymphangiomatosis in children 总被引:14,自引:0,他引:14
89.
90.
Normal and stenotic renal arteries: experimental balloon-expandable intraluminal stenting 总被引:2,自引:0,他引:2
Palmaz JC; Kopp DT; Hayashi H; Schatz RA; Hunter G; Tio FO; Garcia O; Alvarado R; Rees C; Thomas SC 《Radiology》1987,164(3):705-708
Elastic recoil of the vessel wall is a common cause of failure of percutaneous transluminal angioplasty in renal arteries. To oppose such recoil, balloon-expandable metal stents were implanted in artificially stenotic renal arteries in pigs and normal renal arteries in dogs and pigs. The stents were then examined angiographically and histologically at regular intervals. All stents were completely covered with endothelialized neointima in 3 weeks. There was no difference in intimal thickness between the stenotic and nonstenotic renal arteries. A large stent diameter and a large open or nonmetal surface may cause less intimal hyperplasia, but nonturbulent, fast arterial flow is probably the most important factor in ensuring long-term patency of the vessel. 相似文献