Kooperativer Bibliotheksverbund

Berlin Brandenburg


Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

  • Losert, Doris  (7)
Type of Medium
  • 1
    Language: English
    In: Clinical chemistry, April 2004, Vol.50(4), pp.769-72
    Description: The β2-adrenergic receptor (ADRB2) is a GTP-binding-protein-coupled receptor produced by a wide variety of cell types. Stimulation of ADRB2 by catecholamines or synthetic therapeutic agonists promotes physiologic processes as varied as smooth muscle relaxation and lipolysis. Stimulation of ADRB2 is characterized by rapid desensitization governed by receptor internalization, which plays a direct role in the response to catecholamines and synthetic agonists governing cellular responses (1). ADRB2 is transcribed from an intronless gene on chromosome 5q32 that encodes a 413-residue protein with 7 transmembrane domains (2). Within the ADRB2 gene, 13 single-nucleotide polymorphisms (SNPs) have been identified (3), including 3 coding ADRB2 missense polymorphisms that alter protein function (4). A threonine-to-isoleucine (T164I) substitution in the fourth transmembrane domain alters ligand binding and decreases adenylate cyclase activation but is rare in the population (5). The extracellular domain N-terminal arginine-to-glycine (R16G) and glutamine-to-glutamic acid (Q27E) polymorphisms are common and widely distributed within the population. These polymorphisms strongly influence the degree of agonist-mediated receptor down-regulation. Whereas Q27E induces complete resistance to down-regulation in combination with R16, R16G increases agonist-mediated receptor down-regulation in both haplotypes (5). The importance of developing rapid ADRB2 screening protocols that differentiate codon 16/27 diplotypes is emphasized by the number of studies linking these genotypes to clinical and pharmacologic responses. SNPs representing the partial haplotype at codons 16 and 27 are variously associated with altered vasodilation (6) and high blood pressure (7), play roles in the development of type II diabetes (8), and have been linked to preterm delivery (9), agonist desensitization (10), albuterol responses (11), increased IgE in asthmatic families (12), obesity (13), hypertriglyceridemia, and development of fatty liver (14). Methods to routinely detect the common codon 16 and 27 polymorphisms have relied on preliminary amplification of ADRB2 sequences by PCR and subsequent identification by …
    Keywords: Receptors, Adrenergic, Beta-2 -- Genetics
    ISSN: 0009-9147
    E-ISSN: 15308561
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 2
    Language: English
    In: Clinical science (London, England : 1979), January 2006, Vol.110(1), pp.47-58
    Description: Gene silencing by siRNA (short interfering RNA) is a still developing field in biology and has evolved as a novel post-transcriptional gene silencing strategy with therapeutic potential. With siRNAs, virtually every gene in the human genome contributing to a disease becomes amenable to regulation, thus opening unprecedented opportunities for drug discovery. Besides the well-established role for siRNA as a tool for target screening and validation in vitro, recent progress of siRNA delivery in vivo raised expectations for siRNA drugs as the up-and-coming 'magic bullet'. Whether siRNA compounds will make it as novel chemical entities from 'bench to bedside' will probably depend largely on improving their pharmacokinetics in terms of plasma stability and cellular uptake. Whereas locally administered siRNAs have already entered the first clinical trials, strategies for successful systemic delivery of siRNA are still in a preclinical stage of development. Irrespective of its therapeutic potential, RNAi (RNA interference) has unambiguously become a valuable tool for basic research in biology and thereby it will continue to have a major impact on medical science. In this review, we will give a brief overview about the history and current understanding of RNAi and focus on potential applications, especially as a therapeutic option to treat human disease.
    Keywords: Gene Silencing ; RNA, Small Interfering -- Therapeutic Use
    ISSN: 0143-5221
    E-ISSN: 14708736
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 3
    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
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 4
    In: Anti-Cancer Drugs, 2007, Vol.18(7), pp.755-761
    Description: The antiapoptotic protein Bcl-2 contributes to a more chemoresistant phenotype of nonsmall cell lung cancer and therefore serves as an important target for novel anticancer strategies. Interestingly, docetaxel as a standard of care for treatment of nonsmall cell lung cancer has been shown to inactivate the Bcl-2 function by phosphorylation. We investigated the Bcl-2 expression status of nonsmall cell lung cancer cells in response to cisplatin or docetaxel and its effect on sensitizing nonsmall cell lung cancer cells by Bcl-2 downregulation employing a small interfering RNA approach. Bcl-2 expression was assessed by Western blotting and RT-PCR. Cell proliferation and apoptosis of nonsmall cell lung cancer cells were measured by an MTS-based assay and Annexin V/7-Aminoactinomycin, respectively. Combination treatment of Bcl-2 small interfering RNA with cisplatin resulted in a synergistic activity. By contrast, Bcl-2 downregulation did not sensitize nonsmall cell lung cancer cells to docetaxel. Of note, docetaxel treatment resulted in Bcl-2 phosphorylation of nonsmall cell lung cancer cells, whereas cisplatin increased the Bcl-2 overall expression and abrogated Bcl-2 phosphorylation. On the basis of our findings, a Bcl-2 silencing approach appears to be a suitable strategy for sensitizing nonsmall cell lung cancer to cisplatin, but not to docetaxel.
    Keywords: Antineoplastic Agents -- Pharmacology ; Carcinoma, Non-Small-Cell Lung -- Drug Therapy ; Cisplatin -- Pharmacology ; Lung Neoplasms -- Drug Therapy ; Proto-Oncogene Proteins C-Bcl-2 -- Metabolism ; Taxoids -- Pharmacology;
    ISSN: 0959-4973
    E-ISSN: 14735741
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 5
    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
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 6
    Language: English
    In: Oligonucleotides, 2003, Vol.13(5), pp.393-400
    Description: Malignant melanoma is a prime example of a treatment-resistant tumor with poor prognosis. Even with innovative treatment regimens, response rates remain low, and the duration of responses is short. More than 90% of all melanomas express the antiapoptotic protein Bcl-2, shown to contribute to a chemoresistant phenotype in melanoma. We previously demonstrated that antisense-mediated inhibition of Bcl-2 sensitizes malignant melanoma to apoptosis-inducing treatment modalities. In the present study, we evaluated synthetic small interfering RNA (siRNA) compounds targeting Bcl-2 as a novel approach to downregulate Bcl-2 expression in melanoma cells. siRNA treatment led up to a 19-fold reduction of bcl-2 mRNA levels and only barely detectable Bcl-2 protein expression at low nanomolar concentrations. Silencing of Bcl-2 in melanoma cells by specific siRNA led to a moderate increase in apoptotic cell death and inhibition of cell growth. However, if siRNA compounds targeting Bcl-2 were combined with the apoptosis-inducing chemotherapeutic agent cisplatin, a massive increase in apoptotic cell death compared with controls was observed. Notably, the combination of Bcl2 siRNA and low-dose cisplatin resulted in a supra-additive effect, with nearly complete suppression of cell growth, whereas cell growth in cisplatin-only-treated cells was only moderately affected (96% vs. 25%, p 〈 0.001). These findings underline a key role for Bcl-2 in conferring chemoresistance to melanoma and highlight Bcl-2 siRNA strategies as novel and highly effective tools, with the potential for future targeted therapy of malignant melanoma.
    Keywords: Melanoma -- Genetics ; RNA, Small Interfering -- Genetics
    ISSN: 1545-4576
    E-ISSN: 15578526
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
  • 7
    Language: English
    In: Journal of Hepatology, January 2006, Vol.44(1), pp.151-157
    Description: Recently, the anti-apoptotic Mcl-1 protein has been reported as a resistance factor in various types of cancer. Here we investigated the presence of Mcl-1 protein in hepatocellular carcinoma (HCC) tissues and its potential role as a molecular drug target for HCC therapy. HCC specimens of 149 patients were examined by immunohistochemistry for Mcl-1 expression. Antisense oligonucleotides (ASO) targeting Mcl-1 were evaluated as monotherapy and in combination with cisplatin in the HCC cell lines HepG2 and Snu398. Protein regulation, cell viability, and apoptosis were assessed by western blotting, cell counting, and FACS analysis. Mcl-1 protein is overexpressed in 51% of all cases irrespective of underlying disease. Targeting Mcl-1 by ASO specifically downregulated Mcl-1 protein expression and led to significant dose and time dependent single agent activity in HCC cells characterized by increased apoptosis and decreased cell viability. No significant target regulation or cell death was observed for control oligonucleotide treatment. Upon combination with cisplatin, Mcl-1 ASO revealed a significant chemosensitizing effect. Mcl-1 is overexpressed in half of HCC-tissues. ASO targeting Mcl-1 revealed a prominent single agent and chemosensitizing activity against HCC in vitro. Targeting Mcl-1 might qualify as a promising novel approach in HCC therapy.
    Keywords: Hcc ; Mcl-1 ; Targeted Therapy ; Antisense Oligonucleotide ; Medicine
    ISSN: 0168-8278
    E-ISSN: 1600-0641
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. Further information can be found on the KOBV privacy pages