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Berlin Brandenburg

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  • Oligonucleotides, Antisense  (12)
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  • 1
    In: Anti-Cancer Drugs, 2011, Vol.22(3), pp.245-252
    Description: Sphingosine kinase 1 (Sphk1), a lipid kinase implicated in cell transformation and tumor growth, is overexpressed in gastric cancer and is linked with a poor prognosis. The biological relevance of Sphk1 expression in gastric cancer is unclear. Here, we studied the functional significance of Sphk1 as a novel molecular target for gastric cancer by using an antisense oligonucleotide approach in vitro and in vivo.Gastric cancer cell lines (MKN28 and N87) were treated with Sphk1 with locked nucleic acid–antisense oligonucleotides (LNA–ASO). Sphk1 target regulation, cell growth, and apoptosis were assessed for single-agent Sphk1 LNA–ASO and for combinations with doxorubicin. Athymic nude mice xenografted with gastric cancer cells were treated with Sphk1 LNA and assessed for tumor growth and Sphk1 target regulation, in vivo.In vitro, nanomolar concentrations of Sphk1 LNA–ASO induced an approximately two-fold reduction in Sphk1 mRNA in both the cell lines. This resulted in a 1.6-fold increase in apoptosis and inhibited the growth of gastric cancer cells by more than 50% (P〈0.05). The combination of Sphk1 LNA–ASO with doxorubicin resulted in significant chemosensitization. In vivo, Sphk1 LNA–ASO displayed neither mRNA target regulation in xenografts nor antitumor activity in two independent nude mouse xenograft models.In conclusion, the potent single-agent activity and the synergistic effect of Sphk1 LNA–ASO in combination with chemotherapy in vitro highlight Sphk1 as a biologically relevant molecular target for gastric cancer. Further studies are warranted to overcome the challenge of delivering Sphk1-targeting RNA-therapeutics to solid tumors in vivo.
    Keywords: Molecular Targeted Therapy ; Apoptosis -- Drug Effects ; Cell Proliferation -- Drug Effects ; Oligonucleotides, Antisense -- Pharmacology ; Phosphotransferases (Alcohol Group Acceptor) -- Genetics ; Stomach Neoplasms -- Drug Therapy;
    ISSN: 0959-4973
    E-ISSN: 14735741
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  • 2
    Language: English
    In: International journal of cancer, 01 May 2002, Vol.99(1), pp.29-34
    Description: Malignant melanoma is a tumor that responds poorly to a variety of apoptosis-inducing treatment modalities, such as chemotherapy. The expression of genes that regulate apoptotic cell death plays an important role in determining the sensitivity of tumor cells to chemotherapeutic intervention. Bcl-x(L) is an antiapoptotic member of the Bcl-2 family and is universally expressed in human melanoma. To evaluate the Bcl-x(L) protein as a potential therapeutic target in melanoma, the influence of Bcl-x(L) expression levels on the chemoresistance of human melanoma cells was investigated. Overexpression of Bcl-x(L) in stably transfected human melanoma Mel Juso cells significantly reduced sensitivity to cisplatin-induced apoptosis (p 〈 or = 0.05). In a parallel approach, reduction of Bcl-x(L) protein by specific AS oligonucleotide (ISIS 16009) treatment enhanced the chemosensitivity of Mel Juso cells by 62% compared to cells treated with MM control oligonucleotide (ISIS 16967) as well as chemotherapy-induced apoptosis. These data suggest that Bcl-x(L) is an important factor contributing to the chemoresistance of human melanoma. Reduction of Bcl-x(L) expression by AS oligonucleotides provides a rational and promising approach that may help to overcome chemoresistance in this malignancy.
    Keywords: Antineoplastic Agents -- Therapeutic Use ; Apoptosis -- Drug Effects ; Cisplatin -- Therapeutic Use ; Melanoma -- Drug Therapy ; Oligonucleotides, Antisense -- Therapeutic Use ; Proto-Oncogene Proteins C-Bcl-2 -- Antagonists & Inhibitors ; Skin Neoplasms -- Drug Therapy
    ISSN: 0020-7136
    E-ISSN: 10970215
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  • 3
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 15 June 2004, Vol.10(12 Pt 1), pp.4185-91
    Description: Little is known about the role that Mcl-1, an antiapoptotic Bcl-2 family member, plays in solid tumor biology and susceptibility to anticancer therapy. We observed that the Mcl-1 protein is widely expressed in human sarcoma cell lines of different histological origin (n = 7). Because the expression of antiapoptotic Bcl-2 family proteins can significantly contribute to the chemoresistance of human malignancies, we used an antisense strategy to address this issue in sarcoma. SCID mice (n = 6/group) received s.c. injections of SW872 liposarcoma cells. After development of palpable tumors, mice were treated by s.c.-implanted miniosmotic pumps prefilled with saline or antisense or universal control oligonucleotides (20 mg/kg/day for 2 weeks). On days 2, 6, and 10, mice were treated with low-dose cyclophosphamide (35 mg/kg i.p) or saline control. During the experiments, tumor weight was assessed twice weekly by caliper measurements. On day 14, animals were sacrificed. Tumors were weighed and fixed in formalin for immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling analysis. Mcl-1 antisense oligonucleotides specifically reduced Mcl-1 protein expression but produced no reduction in tumor weight compared with saline-treated control animals. Cyclophosphamide monotreatment caused only modest tumor weight reduction compared with saline control. However, use of Mcl-1 antisense oligonucleotides combined with cyclophosphamide clearly enhanced tumor cell apoptosis and significantly reduced tumor weight by more than two-thirds compared with respective control treatments. A combination of Mcl-1 antisense oligonucleotides with low-dose cyclophosphamide provides a synergistic antitumor effect and might qualify as a promising strategy to overcome chemoresistance in human sarcoma.
    Keywords: Drug Resistance, Neoplasm ; Cyclophosphamide -- Therapeutic Use ; Neoplasm Proteins -- Metabolism ; Oligonucleotides, Antisense -- Therapeutic Use ; Proto-Oncogene Proteins C-Bcl-2 -- Metabolism ; Sarcoma -- Drug Therapy
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 4
    Language: English
    In: Blood, 15 April 2005, Vol.105(8), pp.3303-11
    Description: Antiapoptotic members of the bcl-2 family have recently been implicated in the pathogenesis of chronic myeloid leukemia (CML), a hematopoietic neoplasm associated with the BCR/ABL oncogene. We have examined expression of MCL-1 in primary CML cells and BCR/ABL-transformed cell lines. Independent of the phase of disease, isolated primary CML cells expressed myeloid cell leukemia-1 (mcl-1) mRNA and the MCL-1 protein in a constitutive manner. The BCR/ABL inhibitor imatinib (=STI571) decreased the expression of MCL-1 in these cells. Correspondingly, BCR/ABL enhanced mcl-1 promoter activity, mcl-1 mRNA expression, and the MCL-1 protein in Ba/F3 cells. BCR/ABL-dependent expression of MCL-1 in Ba/F3 cells was counteracted by the mitogen-activated protein-kinase/extracellular signal-regulated kinase (MEK) inhibitor, PD98059, but not by the phosphoinositide 3-kinase inhibitor, LY294002. Identical results were obtained for constitutive expression of MCL-1 in primary CML cells and the CML-derived cell lines K562 and KU812. To investigate the role of MCL-1 as a survival-related target in CML cells, mcl-1 siRNA and mcl-1 antisense oligonucleotides (ASOs) were applied. The resulting down-regulation of MCL-1 was found to be associated with a substantial decrease in viability of K562 cells. Moreover, the mcl-1 ASO was found to synergize with imatinib in producing growth inhibition in these cells. Together, our data identify MCL-1 as a BCR/ABL-dependent survival factor and interesting target in CML.
    Keywords: Antineoplastic Agents -- Pharmacology ; Fusion Proteins, Bcr-Abl -- Metabolism ; Leukemia, Myelogenous, Chronic, BCR-Abl Positive -- Drug Therapy ; Neoplasm Proteins -- Metabolism ; Oligonucleotides, Antisense -- Pharmacology ; Piperazines -- Pharmacology ; Proto-Oncogene Proteins C-Bcl-2 -- Metabolism ; Pyrimidines -- Pharmacology
    ISSN: 0006-4971
    E-ISSN: 15280020
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  • 5
    Language: English
    In: Nucleic acids research, 2004, Vol.32(2), pp.710-8
    Description: Conjugation of ligands to antisense oligonucleotides is a promising approach for enhancing their effects. In this report, a new method for synthesizing oligonucleotide conjugates is described. 2'-Amino-2'-deoxy-5'-dimethoxytrityl-uridine was select ively acylated with a succinic acid linker at the 2' position. This compound was incorporated at the 3' end of an oligonucleotide corresponding to the sequence of Oblimersen. The carboxyl group was protected for oligonucleotide synthesis as a benzyl ester, which could be selectively cleaved at the solid phase by a catalytic phase transfer reaction using palladium nanoparticles as catalyst. An oligonucleotide-fluorescein conjugate was prepared by condensation of aminofluorescein. Circular dichroism spectroscopic experiments showed a B-DNA type structure. The melting temperature of the duplex was only slightly lower than that of Oblimersen. Biological activity measured by western blotting resulted in a Bcl-2 target downregulation nearly identical to that of control Oblimersen on human melanoma cells, proving that this method is attractive for the binding of ligands located in the minor groove.
    Keywords: Oligonucleotides, Antisense -- Chemistry ; Uridine -- Analogs & Derivatives
    E-ISSN: 1362-4962
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  • 6
    Language: English
    In: Chemotherapy, September 2002, Vol.48(4), pp.189-195
    Description: Background: Resistance to chemotherapy in glioblastoma has been linked to the expression of antiapoptotic Bcl-2 family members including Bcl-xL. Methods: Bcl-xL expression was specifically reduced in M059K glioblastoma cells with antisense oligonucleotides (ISIS 16009, ISIS 16967) as assessed by Western blotting. Induction of apoptosis by treatment with antisense oligonucleotides in combination with paclitaxel in cell culture was monitored by WST-1 assays and flow cytometric analysis. Results: Antisense oligonucleotide-mediated reduction of Bcl-xL levels led to enhanced cytotoxicity in M059K cells when compared to the use of a mismatch control oligonucleotide (p 〈 0.001). A decreased threshold for the induction of apoptosis led to significantly enhanced cytotoxic responses to paclitaxel treatment in WST-1 assays (p 〈 0.001) and flow cytometric analyses. Conclusion: Combination treatment using Bcl-xL antisense oligonucleotides and paclitaxel may qualify as a promising strategy to ultimately improve the clinical outcome of glioblastoma.
    Keywords: Experimental Chemotherapy ; Glioblastoma ; Antisense Oligonucleotides ; Bcl-Xl ; Paclitaxel ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0009-3157
    E-ISSN: 1421-9794
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  • 7
    Language: English
    In: Anticancer research, 2005, Vol.25(4), pp.2697-703
    Description: Anti-apoptotic Bcl-2 family proteins, such as Bcl-2 and Bcl-x, can modulate radio- and/or chemosensitivity of human malignancies. Since no information is available on the role Mcl-1 may play in the radioresponse of tumor cells, the relationship between Mcl-1 expression and response to ionizing radiation (IR) was investigated using an antisense strategy. Human melanoma cells were treated with Mcl-1 antisense oligonucleotides (ASOs) and IR. The effects of antisense treatment alone or in combination with IR on proliferation, induction of apoptosis and clonogenic cell death were evaluated. ASO treatment in combination with IR reduced the mean cell numbers 9.5-fold compared to a 2.6-fold reduction after ASO treatment alone and a 1.6- fold reduction after IR alone. The percentages of apoptosis measured (means +/- SD) were 49% +/- 3.0 in antisense/IR-treated cultures compared to 1.3% +/- 0.5, 14.3% +/- 0.5, 7.3% +/- 1.1 and 10.3% +/- 0.6 in ASO controls, in antisense-treated, in IR-treated and in antisense control plus IR-treated cells, respectively. Colony formation assays demonstrated a synergistic effect of Mcl-1 down-regulation with IR. Mcl-1 expression affects the radioresistance of human melanoma cells.
    Keywords: Apoptosis -- Radiation Effects ; Melanoma -- Radiotherapy ; Neoplasm Proteins -- Antagonists & Inhibitors ; Oligonucleotides, Antisense -- Genetics ; Proto-Oncogene Proteins C-Bcl-2 -- Antagonists & Inhibitors
    ISSN: 0250-7005
    E-ISSN: 17917530
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 8
    Language: English
    In: Antisense & nucleic acid drug development, December 2002, Vol.12(6), pp.359-67
    Description: The Bcl-2 antisense oligonucleotide (AS-ODN) G3139 chemosensitizes human malignancies by downregulating the antiapoptotic protein Bcl-2. Because G3139 contains two potential immunostimulatory CpG motifs, we asked if immune stimulation contributes to the antitumor activity observed previously. 5'-Methylation of cytosines in CpG motifs abrogates immune stimulation by oligonucleotides. We, therefore, studied the antitumor and immunostimulatory potential of G3139 vs. an identical oligonucleotide, except for methylation of cytosines in the two CpG motifs (G4232). In a human melanoma SCID mouse xenotransplantation model, G3139 or G4232 was administered by continuous subcutaneous (s.c.) or bolus intraperitoneal (i.p.) infusion. Both G3139 and G4232 significantly reduced tumor growth by about one third relative to the saline-treated group. Furthermore, we noted a similar downregulation of Bcl-2 expression and increase in tumor cell apoptosis caused by G3139 and G4232 compared with saline controls. However, mice treated with G3139 had a pronounced increase in spleen weight and interleukin-12 (IL-12) plasma levels relative to mice treated with either G4232 or saline. Splenomegaly and elevated IL-12 plasma levels suggest that G3139 can be immunostimulatory. However, there is clear evidence that the antitumor effect of G3139 in this model appears to be a Bcl-2 antisense effect that is independent of immune stimulation, as G3139 and its immune-silent counterpart G4232 caused similar tumor suppression and apoptosis induction.
    Keywords: Antineoplastic Agents -- Pharmacology ; Cpg Islands -- Immunology ; Genes, Bcl-2 -- Genetics ; Oligonucleotides, Antisense -- Pharmacology ; Thionucleotides -- Pharmacology
    ISSN: 1087-2906
    E-ISSN: 21686599
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  • 9
    Language: English
    In: Cancer Biology & Therapy, 11 October 2006, Vol.5(10), pp.1348-1354
    Description: Gastric cancer is the second most common cause of death from cancer worldwide and resistant to various chemotherapeutic regimens. In gastric cancer, the anti-apoptotic Mcl-1 protein is expressed in up to 75% of all cases and associated with...
    Keywords: Medicine
    ISSN: 1538-4047
    E-ISSN: 1555-8576
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  • 10
    In: Journal of Investigative Dermatology, 2003, Vol.120(6), p.1081
    Description: It is well established that high expression of the antiapoptotic Bcl-2 family proteins Bcl-2 and Bcl-xL can significantly contribute to chemoresistance in a number of human malignancies. Much less is known about the role the more recently described Bcl-2 family member Mcl-1 might play in tumor biology and resistance to chemotherapy. Using an antisense strategy, we here address this issue in melanoma, a paradigm of a treatment-resistant malignancy. After in vitro proof of principle supporting an antisense mechanism of action with specific reduction of Mcl-1 protein as a consequence of nuclear uptake of the Mcl-1 antisense oligonucleotides employed, antisense and universal control oligonucleotides were administered systemically in combination with dacarbazine in a human melanoma SCID mouse xenotransplantation model. Dacarbazine, available now for more than three decades, still remains the most active single agent for treatment of advanced melanoma. Mcl-1 antisense oligonucleotides specifically reduced target protein expression as well as the apoptotic threshold of melanoma xenotransplants. Combined Mcl-1 antisense oligonucleotide plus dacarbazine treatment resulted in enhanced tumor cell apoptosis and led to a significantly reduced mean tumor weight (mean 0.16 g, 95% confidence interval 0.08-0.26) compared to the tumor weight in universal control oligonucleotide plus dacarbazine treated animals (mean 0.35 g, 95% confidence interval 0.2-0.44) or saline plus dacarbazine treated animals (mean 0.39 g, 95% confidence interval 0.25-0.53). We thus show that Mcl-1 is an important factor contributing to the chemoresistance of human melanoma in vivo. Antisense therapy against the Mcl-1 gene product, possibly in combination with antisense strategies targeting other antiapoptotic Bcl-2 family members, appears to be a rational and promising approach to help overcome treatment resistance of malignant melanoma.
    Keywords: Proto-Oncogene Proteins C-Bcl-2 ; Melanoma -- Drug Therapy ; Oligonucleotides, Antisense -- Therapeutic Use ; Skin Neoplasms -- Drug Therapy;
    ISSN: 0022-202X
    E-ISSN: 15231747
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