Antisense & nucleic acid drug development最新文献_第5页

Antitumor mechanisms of oligodeoxynucleotides with CpG and polyG motifs in murine prostate cancer cells: decrease of NF-kappaB and AP-1 binding activities and induction of apoptosis. 具有CpG和polyG基序的寡脱氧核苷酸在小鼠前列腺癌细胞中的抗肿瘤机制:降低NF-kappaB和AP-1结合活性，诱导细胞凋亡。

Antisense & nucleic acid drug development Pub Date : 2002-06-01 DOI: 10.1089/108729002760220752

W. Shen, Marianella Waldschmidt, Xiuqin Zhao, T. Ratliff, A. Krieg

{"title":"Antitumor mechanisms of oligodeoxynucleotides with CpG and polyG motifs in murine prostate cancer cells: decrease of NF-kappaB and AP-1 binding activities and induction of apoptosis.","authors":"W. Shen, Marianella Waldschmidt, Xiuqin Zhao, T. Ratliff, A. Krieg","doi":"10.1089/108729002760220752","DOIUrl":"https://doi.org/10.1089/108729002760220752","url":null,"abstract":"Previous studies have shown that CpG oligodeoxynucleotides (ODNs) have substantial immunostimulatory effects with anticancer applications. The antitumor applications that have been described previously are mediated through the CpG-induced activation of the host immune system, not through direct antitumor effects. Using cytostasis and cell proliferation assays, we demonstrated that specific ODNs inhibit the proliferation of RM-1 cells, a murine prostate cancer cell line. Flow cytometry analysis using propidium iodide (PI) nuclear staining confirmed the direct proapoptotic effect of ODNs on prostate cancer cells. This effect was dose dependent. Further studies using Western blot analysis and electrophoresis mobility shift assay (EMSA) revealed that the treatment of prostate cancer cells with specific ODNs activated the caspase pathway(s) and decreased the binding activities of AP-1 and NF-kappaB in a time-dependent manner. Evaluation of a panel of ODNs containing different DNA motifs demonstrated that the optimal proapoptotic sequences required polyG sequences but that CpG motifs were not essential. Finally, in vivo antitumor studies showed that the proapoptotic polyG motifs significantly inhibited prostate tumor growth. PolyG motifs inhibited tumor growth, and the effects were enhanced by CpG immune activating sequences. ODN containing both polyG and CpG motifs may have enhanced efficacy in tumor therapy through multiple mechanisms of action, including direct antitumor activities and immune activation.","PeriodicalId":7996,"journal":{"name":"Antisense & nucleic acid drug development","volume":"26 1","pages":"155-64"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87318434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 21

Oblimersen Bcl-2 antisense: facilitating apoptosis in anticancer treatment. Oblimersen Bcl-2反义:促进细胞凋亡在抗癌治疗中的作用。

Antisense & nucleic acid drug development Pub Date : 2002-06-01 DOI: 10.1089/108729002760220798

R. Klasa, A. M. Gillum, R. Klem, S. Frankel

{"title":"Oblimersen Bcl-2 antisense: facilitating apoptosis in anticancer treatment.","authors":"R. Klasa, A. M. Gillum, R. Klem, S. Frankel","doi":"10.1089/108729002760220798","DOIUrl":"https://doi.org/10.1089/108729002760220798","url":null,"abstract":"The components of the apoptotic program are targets for anticancer therapy. Bcl-2 protein inhibits apoptosis and confers resistance to treatment with traditional cytotoxic chemotherapy, radiotherapy, and monoclonal antibodies (mAb). Oblimersen sodium (G3139, Genasense, Genta Inc., Berkeley Heights, NJ) is an antisense oligonucleotide (AS-ON) compound designed to specifically bind to the first 6 codons of the human bcl-2 mRNA sequence, resulting in degradation of bcl-2 mRNA and subsequent decrease in Bcl-2 protein translation. Oblimersen is the first oligonucleotide to demonstrate proof of principle of an antisense effect in human tumors by the documented downregulation of the target Bcl-2 protein. A growing body of preclinical and clinical evidence suggests that oblimersen synergizes with many cytotoxic and biologic/immunotherapeutic agents against a variety of hematologic malignancies and solid tumors. Randomized clinical trials are currently underway to evaluate the efficacy and tolerability of oblimersen in combination with cytotoxic chemotherapy in chronic lymphocytic leukemia, multiple myeloma, malignant melanoma, and non-small cell lung cancer. In addition, nonrandomized trials are under way to evaluate oblimersen in non-Hodgkin's lymphoma, acute myeloid leukemia, and hormone-refractory prostate cancer. Preclinical data also support the clinical evaluation of oblimersen in additional tumor types, including chronic myelogenous leukemia and breast, small cell lung, gastric, colon, bladder, and Merkel cell cancers. Enhancement of the efficacy of anticancer treatments with oblimersen Bcl-2 antisense therapy represents a promising new apoptosis-modulating strategy, and ongoing clinical trials will test this therapeutic approach.","PeriodicalId":7996,"journal":{"name":"Antisense & nucleic acid drug development","volume":"61 1","pages":"193-213"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85596089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 274

Highly immunostimulatory CpG-free oligodeoxynucleotides for activation of human leukocytes. 高度免疫刺激CpG-free寡脱氧核苷酸激活人白细胞。

Antisense & nucleic acid drug development Pub Date : 2002-06-01 DOI: 10.1089/108729002760220761

J. Vollmer, Andrea Janosch, Meike Laucht, Z. Ballas, C. Schetter, A. Krieg

{"title":"Highly immunostimulatory CpG-free oligodeoxynucleotides for activation of human leukocytes.","authors":"J. Vollmer, Andrea Janosch, Meike Laucht, Z. Ballas, C. Schetter, A. Krieg","doi":"10.1089/108729002760220761","DOIUrl":"https://doi.org/10.1089/108729002760220761","url":null,"abstract":"Synthetic oligodeoxynucleotides (ODNs) bearing CpG dinucleotides can mimic the immunostimulatory effects of bacterial DNA in vertebrates. Besides the known CpG motifs, no other sequence motif has been shown to have independent immunostimulatory effects. Several past investigators have demonstrated that the nucleotide content or the phosphorothioate (PS) backbone may have effects independently of the sequence. However, the effect of both nucleotide content and PS backbone to stimulate human leukocytes is not well understood. We investigated the immunostimulatory activity of 34 PS-ODNs with different nucleotide contents, lengths, and methylation status on human leukocytes. The thymidine content showed strong CpG-independent contribution to immunostimulation. In contrast, ODNs rich in other nucleotides (guanosine, cytosine, or adenosine) induced no or much lower levels of immunostimulation. The observed effects were highly dependent on the PS backbone chemistry. In addition to the base content and the backbone chemistry, the length of the PS-ODN was directly related to the magnitude of its stimulatory effects, especially on B cells. In addition, methylation of CpG dinucleotides did not always cause an abrogation of the immunostimulation. Immunostimulatory effects could be observed with methylated CpG ODNs, specifically as the ODN length was increased from 18 to 24 or more nucleotides (nt). In contrast, PS-ODNs with inverted CpG dinucleotides showed some but only weak immunostimulation. Our results demonstrate that non-CpG ODNs rich in thymidine or ODNs with methylated CpG motifs have length-dependent immunostimulatory effects. Such ODNs can induce effects similar to those seen with CpG ODNs but are much less efficient in stimulating human immune cells.","PeriodicalId":7996,"journal":{"name":"Antisense & nucleic acid drug development","volume":"37 1","pages":"165-75"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79880032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 68

Advantages of antisense drugs for the treatment of oral diseases. 反义药物治疗口腔疾病的优势。

Antisense & nucleic acid drug development Pub Date : 2002-06-01 DOI: 10.1089/108729002760220789

W. Nedbal, B. Teichmann

{"title":"Advantages of antisense drugs for the treatment of oral diseases.","authors":"W. Nedbal, B. Teichmann","doi":"10.1089/108729002760220789","DOIUrl":"https://doi.org/10.1089/108729002760220789","url":null,"abstract":"For almost two decades, antisense oligonucleotides (AS-ON) have been used successfully to suppress and regulate gene expression in vitro and in vivo. They are, meanwhile, well established to serve as molecular tools for several biologic applications, from the study of single gene functions up to complex target gene validations. Based on an at least theoretically simple mode of action, the sequence-specific inhibition of mRNA functions after complex formation by Watson-Crick base pairing and presumably enzymatic degradation of the target mRNA, they obviously carry a high therapeutic potential for the treatment of human diseases. In recent years, a remarkable number of clinical trials have been initiated and performed to evaluate the therapeutic usefulness of antisense technology. However, after the successful development of the first antisense-based drug Vitravene (Isis Pharmaceutical Inc., Carlsbad, CA) in 1998, no second product has appeared on the market to date. Here, we describe substantial advantages for the development of antisense-based drugs against less severe oral diseases that represent novel but highly promising application fields of the technology.","PeriodicalId":7996,"journal":{"name":"Antisense & nucleic acid drug development","volume":"210 1","pages":"183-91"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73777103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

Efficiency of antisense oligonucleotide drug discovery. 反义寡核苷酸药物的发现效率。

Antisense & nucleic acid drug development Pub Date : 2002-06-01 DOI: 10.1089/108729002760220806

C. Bennett

{"title":"Efficiency of antisense oligonucleotide drug discovery.","authors":"C. Bennett","doi":"10.1089/108729002760220806","DOIUrl":"https://doi.org/10.1089/108729002760220806","url":null,"abstract":"The costs for discovering and developing new drugs continue to escalate, with current estimates that the average cost is more than $800 million for each new drug brought to the market. Pharmaceutical companies are under enormous pressure to increase their efficiency for bringing new drugs to the market by third-party payers, shareholders, and their patients, and at the same time regulators are placing increased demands on the industry. To be successful in the future, pharmaceutical companies must change how they discover and develop new drugs. So far, new technologies have done little to increase overall efficiency of the industry and have added additional costs. Platform technologies such as monoclonal antibodies and antisense oligonucleotides have the potential of reducing costs for discovery of new drugs, in that many of the steps required for traditional small molecules can be skipped or streamlined. Additionally the success of identifying a drug candidate is much higher with platform technologies compared to small molecule drugs. This review will highlight some of the efficiencies of antisense oligonucleotide drug discovery compared to traditional drugs and will point out some of the current limitations of the technology.","PeriodicalId":7996,"journal":{"name":"Antisense & nucleic acid drug development","volume":"222 1","pages":"215-24"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74941389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 33

Pharmacokinetics and tissue distribution of a peptide nucleic acid after intravenous administration. 静脉给药后肽核酸的药代动力学和组织分布。

Antisense & nucleic acid drug development Pub Date : 2002-04-01 DOI: 10.1089/108729002760070803

B. McMahon, D. Mays, J. Lipsky, J. Stewart, A. Fauq, E. Richelson

{"title":"Pharmacokinetics and tissue distribution of a peptide nucleic acid after intravenous administration.","authors":"B. McMahon, D. Mays, J. Lipsky, J. Stewart, A. Fauq, E. Richelson","doi":"10.1089/108729002760070803","DOIUrl":"https://doi.org/10.1089/108729002760070803","url":null,"abstract":"Peptide nucleic acids (PNAs) are DNA analogs that hybridize to complementary nucleic sequences with high affinity and stability. In our previous work, we showed that a PNA complementary to a 12-base pair (bp) sequence of the coding region of the rat neurotensin receptor (rNTR1) mRNA is effective in significantly blocking a rat's central responses to neurotensin (NT), even when the PNA is injected intraperitoneally (i.p.). Using a novel gel shift detection assay to detect PNA, we have now used this same PNA sequence to derive its pharmacokinetic variables and its tissue distribution in the rat. The PNA has a distribution half-life of 3 +/- 3 minutes and an elimination half-life of 17 +/- 3 minutes. The total plasma clearance and volume of distribution of this PNA were 3.4 +/- 0.9 ml/min x kg and 60 +/- 30 ml/kg. Two hours after dosing, the PNA was found at detectable but low levels in all organs examined-in order of decreasing concentration: kidney, liver, heart, brain, and spleen. Approximately 90% of the PNA dose was recovered as unchanged parent compound in the urine 24 hours after administration.","PeriodicalId":7996,"journal":{"name":"Antisense & nucleic acid drug development","volume":"62 1","pages":"65-70"},"PeriodicalIF":0.0,"publicationDate":"2002-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87880228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 89

Carboranyl oligonucleotides: 4. synthesis and physicochemical studies of oligonucleotides containing 2'-O-(o-carboran-1-yl)methyl group. 碳硼基寡核苷酸:4;含2′- o- (o-碳硼-1-基)甲基寡核苷酸的合成及理化研究。

Antisense & nucleic acid drug development Pub Date : 2002-04-01 DOI: 10.1089/108729002760070821

A. Olejniczak, M. Koziołkiewicz, Z. Leśnikowski

{"title":"Carboranyl oligonucleotides: 4. synthesis and physicochemical studies of oligonucleotides containing 2'-O-(o-carboran-1-yl)methyl group.","authors":"A. Olejniczak, M. Koziołkiewicz, Z. Leśnikowski","doi":"10.1089/108729002760070821","DOIUrl":"https://doi.org/10.1089/108729002760070821","url":null,"abstract":"Boronated oligonucleotides are potential candidates for antisense oligonucleotide technology (AOT), boron neutron capture therapy (BNCT), and as tools in molecular biology. A method was developed for the solid phase synthesis of oligonucleotides containing 2'-O-(o-carboran-1-yl-methyl) (2'-CBM) group. Synthesis was performed using a standard beta-cyanoethyl cycle and automated DNA synthesizer. Manual steps were performed for the insertion of a modified monomer bearing the 2'-CBM group. Several tetradecanucleotides complementary to DNA-HCMV, and bearing 2'-CBM modification near the 3'-end or 5'-end or in the middle of the oligonucleotide chain were synthesized. The resulting oligomers were characterized by polyacrylamide gel electrophoresis (PAGE), reverse phase high-performance liquid chromatography (RP-HPLC), matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) and ultraviolet spectroscopy (UV), circular dichroism (CD), and melting temperature (Tm) measurements. Tm of duplexes formed between 2'-CBM-modified tetradecanucleotides and complementary DNA and RNA template were compared with those formed by the unmodified oligonucleotide and complementary sequence. The stability of 2'-CBM oligonucleotides in the presence of phosphodiesterase I from Crotalus atrox venom and in human serum was studied. Oligonucleotides bearing the 2'-CBM group are characterized by increased resistance to enzymatic digestion, increased lipophilicity, and the ability to form stable duplexes with complementary templates.","PeriodicalId":7996,"journal":{"name":"Antisense & nucleic acid drug development","volume":"8 1","pages":"79-94"},"PeriodicalIF":0.0,"publicationDate":"2002-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88758687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 27

Evidence for sequence-dependent and reversible nonspecific effects of PS-capped antisense treatment after intracerebral administration. 脑内给药后ps封帽反义治疗序列依赖和可逆非特异性效应的证据。

Antisense & nucleic acid drug development Pub Date : 2002-04-01 DOI: 10.1089/108729002760070830

S. Boye, A. Pradhan, R. Grant, P. Clarke

{"title":"Evidence for sequence-dependent and reversible nonspecific effects of PS-capped antisense treatment after intracerebral administration.","authors":"S. Boye, A. Pradhan, R. Grant, P. Clarke","doi":"10.1089/108729002760070830","DOIUrl":"https://doi.org/10.1089/108729002760070830","url":null,"abstract":"Phosphorothioate (PS)-capped phosphodiester (PE) oligodeoxynucleotides (ODNs) were used to determine whether the dopamine-dependent locomotor-stimulant effect of nicotine is mediated via a4 subunit-containing nicotinic receptors. To this end, rats received direct intraventral tegmental area infusion of a4 antisense via osmotic minipump, and their locomotor response to nicotine (0.2 mg/kg, s.c.) was tested. Eight antisense ODNs were screened, but only one inhibited nicotine-induced locomotion. This inhibition was reversible and selective, insofar as basal (saline) activity was unaffected, and a mismatch ODN was without effect. However, antisense treatment also caused sequence-dependent toxic effects, including neuronal degeneration in the ventral tegmental area, dopaminergic denervation, and weight loss. We conclude that despite previous reports, PS-capped PE-ODNs can cause severe neurotoxicity on chronic infusion into brain tissue. Moreover, sequence dependence and temporal reversibility, two generally accepted criteria of antisense action, may sometimes reflect the occurrence of toxic effects and resultant functional compensation.","PeriodicalId":7996,"journal":{"name":"Antisense & nucleic acid drug development","volume":"16 1","pages":"95-102"},"PeriodicalIF":0.0,"publicationDate":"2002-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77946591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 6

Cell-dependent differential cellular uptake of PNA, peptides, and PNA-peptide conjugates. 细胞依赖的PNA、多肽和PNA-肽偶联物的细胞摄取差异。

Antisense & nucleic acid drug development Pub Date : 2002-04-01 DOI: 10.1089/108729002760070795

U. Koppelhus, S. Awasthi, V. Zachar, H. U. Holst, P. Ebbesen, P. Nielsen

{"title":"Cell-dependent differential cellular uptake of PNA, peptides, and PNA-peptide conjugates.","authors":"U. Koppelhus, S. Awasthi, V. Zachar, H. U. Holst, P. Ebbesen, P. Nielsen","doi":"10.1089/108729002760070795","DOIUrl":"https://doi.org/10.1089/108729002760070795","url":null,"abstract":"Peptide nucleic acid (PNA) oligomers were conjugated to cell-penetrating peptides: pAnt, a 17-residue fragment of the Drosophila protein Antennapedia, and pTat, a 14-amino acid fragment of HIV protein Tat. A 14-mer PNA was attached to the peptide by disulfide linkage or by maleimide coupling. The uptake of (directly or indirectly, via biotin) fluorescein-labeled peptides, PNAs, or PNA-peptide conjugates was studied by fluorescence microscopy, confocal laser scanning microscopy, and fluorometry in five cell types. In SK-BR-3, HeLa, and IMR-90 cells, the PNA-peptide conjugates and a T1, backbone-modified PNA were readily taken up (2 microM). The PNA was almost exclusively confined to vesicular compartments in the cytosol. However, the IMR-90 cells also showed a weak diffuse staining of the cytoplasm. In the U937 cells, we observed a very weak and exclusively vesicular staining with the PNA-peptide conjugates and the T(lys)-modified PNA. No evident uptake of the unmodified PNA was seen. In H9 cells, both peptides and the PNA-peptide conjugates quickly associated with the membrane, followed by a weak intracellular staining. A cytotoxic effect resulting in artificial staining of the cells was observed with fluoresceinated peptides and PNA-peptide conjugates at concentrations above 5-10 microM, depending on cell type and incubation time. We conclude that uptake of PNAs in many cell types can be achieved either by conjugating to certain peptides or simply by charging the PNA backbone using lysine PNA units. The uptake is time, temperature, and concentration dependent and mainly endocytotic. Our results also show that proper controls for cytotoxicity should always be carried out to avoid misinterpretation of visual data.","PeriodicalId":7996,"journal":{"name":"Antisense & nucleic acid drug development","volume":"149 1","pages":"51-63"},"PeriodicalIF":0.0,"publicationDate":"2002-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83812026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 198

Antisense-mediated inhibition of ICAM-1 expression: a therapeutic strategy against inflammation of human periodontal tissue. 反义介导的ICAM-1表达抑制:对抗人类牙周组织炎症的治疗策略。

Antisense & nucleic acid drug development Pub Date : 2002-04-01 DOI: 10.1089/108729002760070812

W. Nedbal, P. Tomakidi, M. J. Lehmann, C. Dörfer, A. Kohl, G. Sczakiel

{"title":"Antisense-mediated inhibition of ICAM-1 expression: a therapeutic strategy against inflammation of human periodontal tissue.","authors":"W. Nedbal, P. Tomakidi, M. J. Lehmann, C. Dörfer, A. Kohl, G. Sczakiel","doi":"10.1089/108729002760070812","DOIUrl":"https://doi.org/10.1089/108729002760070812","url":null,"abstract":"Periodontal diseases, such as gingivitis and periodontitis, are caused by a mixed infection by several types of bacteria in the dental plaque, causing a chronic inflammation of the gingival mucosa. Inflammatory processes in conjunction with immune responses to bacterial attacks are generally protective. In profound periodontitis, however, hyperresponsiveness and hypersensitivity of the immune system are counterproductive because of the destruction of the affected periodontal connective tissues. The intercellular adhesion molecule type 1 (ICAM-1) plays a key role in the onset and manifestation of inflammatory responses. Thus, inhibition of ICAM-1 expression could be of therapeutic relevance for the treatment of destructive periodontitis. Here, antisense oligonucleotides (AS-ON) directed against ICAM-1 suppress protein expression and mRNA levels specifically and effectively in primary human endothelial cells of different tissue origin. Moreover, downregulation of ICAM-1 expression is also observed in AS-ON-transfected inflamed gingival mucosal tissue of patients with periodontal diseases. This work strongly suggests exploiting the local topical application of ICAM-1-directed AS-ON as a therapeutic tool against inflammatory processes of the human gingiva.","PeriodicalId":7996,"journal":{"name":"Antisense & nucleic acid drug development","volume":"80 1","pages":"71-8"},"PeriodicalIF":0.0,"publicationDate":"2002-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88272425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 14