Hans S Poulsen

Copenhagen University Hospital, København, Capital Region, Denmark

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Publications (34)157.67 Total impact

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    ABSTRACT: Small cell lung cancer (SCLC) is an aggressive disease with high mortality, and the identification of effective pharmacological strategies to target SCLC biology represents an urgent need. Using a high-throughput cellular screen of a diverse chemical library, we observe that SCLC is sensitive to transcription-targeting drugs, in particular to THZ1, a recently identified covalent inhibitor of cyclin-dependent kinase 7. We find that expression of super-enhancer-associated transcription factor genes, including MYC family proto-oncogenes and neuroendocrine lineage-specific factors, is highly vulnerability to THZ1 treatment. We propose that downregulation of these transcription factors contributes, in part, to SCLC sensitivity to transcriptional inhibitors and that THZ1 represents a prototype drug for tailored SCLC therapy. Copyright © 2014 Elsevier Inc. All rights reserved.
    Cancer Cell 12/2014; 26(6):909-22. DOI:10.1016/j.ccell.2014.10.019 · 23.89 Impact Factor
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    ABSTRACT: ObjectivesBrain tumor imaging is challenging. Although 18F-FET PET is widely used in the clinic, the value of 18F-FET MicroPET to evaluate brain tumors in xenograft has not been assessed to date. The aim of this study therefore was to evaluate the performance of in vivo 18F-FET MicroPET in detecting a treatment response in xenografts. In addition, the correlations between the 18F-FET tumor accumulation and the gene expression of Ki67 and the amino acid transporters LAT1 and LAT2 were investigated. Furthermore, Ki67, LAT1 and LAT2 gene expression in xenograft and archival patient tumors was compared.MethodsHuman GBM cells were injected orthotopically in nude mice and 18F-FET uptake was followed by weekly MicroPET/CT. When tumor take was observed, mice were treated with CPT-11 or saline weekly. After two weeks of treatment the brain tumors were isolated and quantitative polymerase chain reaction were performed on the xenograft tumors and in parallel on archival patient tumor specimens.ResultsThe relative tumor-to-brain (T/B) ratio of SUVmax was significantly lower after one week (123±6%, n = 7 vs. 147±6%, n = 7; p = 0.018) and after two weeks (142±8%, n = 5 vs. 204±27%, n = 4; p = 0.047) in the CPT-11 group compared with the control group. Strong negative correlations between SUVmax T/B ratio and LAT1 (r = −0.62, p = 0.04) and LAT2 (r = −0.67, p = 0.02) were observed. In addition, a strong positive correlation between LAT1 and Ki67 was detected in xenografts. Furthermore, a 1.6 fold higher expression of LAT1 and a 23 fold higher expression of LAT2 were observed in patient specimens compared to xenografts.Conclusions18F-FET MicroPET can be used to detect a treatment response to CPT-11 in GBM xenografts. The strong negative correlation between SUVmax T/B ratio and LAT1/LAT2 indicates an export transport function. We suggest that 18F-FET PET may be used for detection of early treatment response in patients.
    PLoS ONE 06/2014; 9(6):e100009. DOI:10.1371/journal.pone.0100009 · 3.53 Impact Factor
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    ABSTRACT: Transcriptional targeted suicide gene (SG) therapy driven by the insulinoma-associated 1 (INSM1) promoter makes it possible to target suicide toxin production and cytotoxicity exclusively to small cell lung cancer (SCLC) cells and tumors. It remains to be determined whether acquired chemoresistance, as observed in the majority of SCLC patients, desensitizes SCLC cells to INSM1 promoter-driven SG therapy. A panel of SCLC cell lines resistant to clinically relevant chemotherapeutics was characterized regarding the expression of proteins involved in response to chemotherapy and regarding INSM1 promoter activity. Sensitivity towards INSM1 promoter-driven SG therapy was tested using different systems: Yeast cytosine deaminase-uracil phosphoribosyl transferase (YCD-YUPRT) in combination with the prodrug 5-fluorocytosine (5-FC) or Escherichia coli nitroreductase (NTR) together with the bromomustard prodrug SN27686. The chemoresistant cell lines displayed heterogeneous expression profiles of molecules involved in multidrug resistance, apoptosis and survival pathways. Despite this, the INSM1 promoter activity was found to be unchanged or increased in SCLC chemoresistant cells and xenografts compared to chemosensitive variants. INSM1 promoter-driven SG therapy with YCD-YUPRT/5-FC or NTR/SN27686, was found to induce high levels of cytotoxicity in both chemosensitive and chemoresistant SCLC cells. Moreover, the combination of INSM1 promoter-driven YCD-YUPRT/5-FC therapy and chemotherapy, as well as the combination of INSM1 promoter-driven YCD-YUPRT/5-FC and NTR/SN27686 therapy, was observed to be superior to single agent therapy in chemoresistant SCLC cells. Collectively, the present study demonstrates that targeted SG therapy is a potent therapeutic approach for chemoresistant SCLC patients, with the highest efficacy achieved when applied as combination SG therapy or in combination with standard chemotherapy.
    The Journal of Gene Medicine 07/2012; 14(7):445-58. DOI:10.1002/jgm.2630 · 1.95 Impact Factor
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    ABSTRACT: The combination of irinotecan and bevacizumab has shown efficacy in the treatment of recurrent glioblastoma multiforme (GBM). A prospective, phase II study of 85 patients with various recurrent brain tumors was carried out. Primary endpoints were progression free survival (PFS) and response rate. Patients with recurrent primary brain tumors with performance status 0-2 were eligible. Intravenous bevacizumab 10 mg/kg and irinotecan 125/340 mg/m(2) were administered every 14 days. Evaluation was carried out every eight weeks using MRI and Macdonald response criteria. Treatment was continued until progression. In total 85 patients were included with the following histologies: GBM (n = 32), glioma WHO gr. III (n = 33), glioma WHO gr. II (n = 12) and others (n = 8). Patients received a median of four cycles. ORR (overall response rate) for glioblastoma was 25% and 59% achieved stable disease (SD). Median PFS was 5.2 months. For grade III gliomas ORR was 21% and 45% had SD. Median PFS was 3.7 months. No objective responses occurred in grade II gliomas. In the non-glioma population, one PR as well as several long PFS times were observed. The combination of bevacizumab and irinotecan is well tolerated and moderately efficacious in glioblastoma and glioma WHO gr. III. A majority of patients achieve at least disease stabilization. Prolonged progression-free survival in non-glioma patients warrants further research.
    Acta oncologica (Stockholm, Sweden) 05/2012; 51(6):797-804. DOI:10.3109/0284186X.2012.681063 · 3.71 Impact Factor
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    ABSTRACT: The epidermal growth factor receptor (EGFR) is over-expressed, as well as mutated, in many types of cancers. In particular, the EGFR variant type III mutant (EGFRvIII) has attracted much attention as it is frequently and exclusively found on many tumor cells, and hence both EGFR and EGFRvIII have been proposed as valid targets in many cancer therapy settings. Different strategies have been developed in order to either inhibit EGFR/EGFRvIII activity or to ablate EGFR/EGFRvIII-positive tumor cells. Drugs that inhibit these receptors include monoclonal antibodies (mAbs) that bind to the extracellular part of EGFR, blocking the binding sites for the EGFR ligands, and intracellular tyrosine kinase inhibitors (TKIs) that block the ATP binding site of the tyrosine kinase domain. Besides an EGFRvIII-targeted vaccine, conjugated anti-EGFR mAbs have been used in different settings to deliver lethal agents to the EGFR/EGFRvIII-positive cells; among these are radio-labelled mAbs and immunotoxins. This article reviews the current status and efficacy of EGFR/EGFRvIII-targeted therapies.
    BioDrugs 04/2012; 26(2):83-99. DOI:10.2165/11599760-000000000-00000 · 2.12 Impact Factor
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    Roza Zandi, Kai Xu, Hans S Poulsen, Jack A Roth, Lin Ji
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    ABSTRACT: The candidate tumor suppressor fragile histidine traid (FHIT) is frequently inactivated in small cell lung cancer (SCLC). Mutations in the p53 gene also occur in the majority of SCLC leading to the accumulation of the mutant protein. Here we evaluated the effect of FHIT gene therapy alone or in combination with the mutant p53-reactivating molecule, PRIMA-1(Met)/APR-246, in SCLC. Overexpression of FHIT by recombinant adenoviral vector (Ad-FHIT)-mediated gene transfer in SCLC cells inhibited their growth by inducing apoptosis and when combined with PRIMA-1(Met)/APR-246, a synergistic cell growth inhibition was achieved.
    Cancer Investigation 11/2011; 29(10):683-91. DOI:10.3109/07357907.2011.626475 · 2.06 Impact Factor
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    ABSTRACT: Small cell lung cancer (SCLC) is a highly malignant disease with poor prognosis, necessitating the need to develop new and efficient treatment modalities. PRIMA-1(Met) (p53-dependent reactivation of massive apoptosis), also known as APR-246, is a small molecule, which restores tumor suppressor function to mutant p53 and induces cancer cell death in various cancer types. Since p53 is mutated in more than 90% of SCLC, we investigated the ability of PRIMA-1(Met) to induce apoptosis and inhibit tumor growth in SCLC with different p53 mutations. The therapeutic effect of PRIMA-1(Met)/APR-246 was studied in SCLC cells in vitro using cell viability assay, fluorescence-activated cell-sorting analysis, p53 knockdown studies, and Western blot analyses. The antitumor potential of PRIMA-1(Met)/APR-246 was further evaluated in two different SCLC xenograft models. PRIMA-1(Met)/APR-246 efficiently inhibited the growth of the SCLC cell lines expressing mutant p53 in vitro and induced apoptosis, associated with increased fraction of cells with fragmented DNA, caspase-3 activation, PARP cleavage, Bax and Noxa upregulation and Bcl-2 downregulation in the cells. The growth suppressive effect of PRIMA-1(Met)/APR-246 was markedly reduced in SCLC cell lines transfected with p53 siRNA, supporting the role of mutant p53 in PRIMA-1(Met)/APR-246-induced cell death. Moreover, in vivo studies showed significant antitumor effects of PRIMA-1(Met) after i.v. injection in SCLC mouse models with no apparent toxicity. This study is the first to show the potential use of p53-reactivating molecules such as PRIMA-1(Met)/APR-246 for the treatment of SCLC.
    Clinical Cancer Research 03/2011; 17(9):2830-41. DOI:10.1158/1078-0432.CCR-10-3168 · 8.19 Impact Factor
  • Roza Zandi, Kai Xu, Hans S. Poulsen, Jack A Roth, Lin Ji
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    ABSTRACT: FUS1, also known as tumor suppressor candidate 2 (TUSC2), is a novel candidate tumor suppressor gene (TSG) frequently inactivated in human lung cancer. Loss of FUS1 protein expression is found in almost all small cell lung cancer (SCLC) cell lines and tumor specimens. Therefore, restoration of normal FUS1 function by gene transfer could serve as a potential therapeutic strategy for the treatment of SCLC. Here we investigated the effect of exogenous expression of FUS1 by plasmid-mediated gene transfer on tumor cell growth and apoptosis induction in FUS1-defective SCLC cells. Transfection of SCLC cells with wild-type FUS1 (wt-FUS1) showed in vitro growth inhibition and a marked suppression of colony formation compared to cells transfected with an empty vector (EV) or a myristoylation-defect mutant FUS1 (mt-FUS1). Forced expression of wt-FUS1 also increased the apoptotic cell population at Sub-G0/G1 in SCLC cells compared to EV- and mt-FUS1-transfected controls, which was associated with a decreased level of pro-caspase-3 and an increased level of PARP cleavage. Our results demonstrate the potential tumor suppression function of FUS1 in SCLC cells and suggest that FUS1-mediated gene therapy could be a useful therapeutic strategy for the treatment of SCLC.
    Clinical and experimental pathology 01/2011; DOI:10.4172/2161-0681.S5-001
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    ABSTRACT: Overexpression and/or amplification of the epidermal growth factor receptor (EGFR) is present in 35-45% of primary glioblastoma multiforme tumors and has been correlated with a poor prognosis. In this study, we investigated the effect of cetuximab and intracellular signaling pathways downstream of EGFR, important for cell survival and proliferation. We show insufficient EGFR downregulation and competition with endogenous EGFR ligands upon cetuximab treatment. Dose-response experiments showed inhibition of EGFR phosphorylation without affecting two of the prominent downstream signaling pathways. Our results indicate that amplification and/or overexpression of EGFR is an unsatisfactory predictor for response to cetuximab.
    Cancer Investigation 10/2010; 28(8):775-87. DOI:10.3109/07357907.2010.483506 · 2.06 Impact Factor
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    ABSTRACT: Malignant gliomas, the deadliest of brain neoplasms, show rampant genetic instability and resistance to genotoxic therapies, implicating potentially aberrant DNA damage response (DDR) in glioma pathogenesis and treatment failure. Here, we report on gross, aberrant constitutive activation of DNA damage signalling in low- and high-grade human gliomas, and analyze the sources of such endogenous genotoxic stress. Based on analyses of human glioblastoma multiforme (GBM) cell lines, normal astrocytes and clinical specimens from grade II astrocytomas (n=41) and grade IV GBM (n=60), we conclude that the DDR machinery is constitutively activated in gliomas, as documented by phosphorylated histone H2AX (gammaH2AX), activation of the ATM-Chk2-p53 pathway, 53BP1 foci and other markers. Oxidative DNA damage (8-oxoguanine) was high in some GBM cell lines and many GBM tumors, while it was low in normal brain and grade II astrocytomas, despite the degree of DDR activation was higher in grade II tumors. Markers indicative of ongoing DNA replication stress (Chk1 activation, Rad17 phosphorylation, replication protein A foci and single-stranded DNA) were present in GBM cells under high- or low-oxygen culture conditions and in clinical specimens of both low- and high-grade tumors. The observed global checkpoint signaling, in contrast to only focal areas of overabundant p53 (indicative of p53 mutation) in grade II astrocytomas, are consistent with DDR activation being an early event in gliomagenesis, initially limiting cell proliferation (low Ki-67 index) and selecting for mutations of p53 and likely other genes that allow escape (higher Ki-67 index) from the checkpoint and facilitate tumor progression. Overall, these results support the potential role of the DDR machinery as a barrier to gliomagenesis and indicate that replication stress, rather than oxidative stress, fuels the DNA damage signalling in early stages of astrocytoma development.
    Oncogene 09/2010; 29(36):5095-102. DOI:10.1038/onc.2010.249 · 8.56 Impact Factor
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    ABSTRACT: Small cell lung cancer (SCLC) is a highly malignant cancer for which there is no curable treatment. Novel therapies are therefore in great demand. In the present study we investigated the therapeutic effect of transcriptionally targeted suicide gene therapy for SCLC based on the yeast cytosine deaminase (YCD) gene alone or fused with the yeast uracil phosphoribosyl transferase (YUPRT) gene followed by administration of 5-fluorocytosine (5-FC) prodrug. Experimental design: The YCD gene or the YCD-YUPRT gene was placed under regulation of the SCLC-specific promoter insulinoma-associated 1 (INSM1). Therapeutic effect was evaluated in vitro in SCLC cell lines and in vivo in SCLC xenografted nude mice using the nonviral nanoparticle DOTAP/cholesterol for transgene delivery. INSM1-YCD/5-FC and INSM1-YCD-YUPRT/5-FC therapy induced high cytotoxicity in a range of SCLC cell lines. The highest therapeutic effect was obtained from the YCD-YUPRT fusion gene strategy. No cytotoxicity was induced after treatment of cell lines of other origin than SCLC. In addition the INSM1-YCD-YUPRT/5-FC therapy was superior to an established suicide gene system consisting of the herpes simplex virus thymidine kinase (HSVTK) gene and the prodrug ganciclovir. The superior effect was in part due to massive bystander cytotoxicity of YCD-YUPRT-produced toxins. Finally, INSM1-YCD-YUPRT/5-FC therapy induced significant tumor growth delay in SCLC xenografts compared with control-treated xenografts. The current study is the first to test cytosine deaminase-based suicide gene therapy for SCLC and the first to show an antitumor effect from the delivery of suicide gene therapeutics for SCLC in vivo.
    Clinical Cancer Research 04/2010; 16(8):2308-19. DOI:10.1158/1078-0432.CCR-09-3057 · 8.19 Impact Factor
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    ABSTRACT: Small-cell lung cancer (SCLC) is a highly malignant disease with poor prognosis. Hence, there is great demand for new therapies that can replace or supplement the current available treatment regimes. Gene therapy constitutes a promising strategy and relies on the principle of introducing exogenous DNA into malignant cells causing them to die. Since SCLC is a highly disseminated malignancy, the gene therapeutic agent must be administered systemically, obligating a high level of targeting of tumor tissue and the use of delivery vehicles designed for systemic circulation of the therapeutic DNA. This review describes and discusses the current status of the application of gene therapy in relation to SCLC.
    Expert Review of Anti-infective Therapy 05/2009; 9(4):437-52. DOI:10.1586/era.09.10 · 2.28 Impact Factor
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    ABSTRACT: Protein Gene Product 9.5 (PGP9.5) is highly expressed in nervous tissue. Recently PGP9.5 expression has been found to be upregulated in the pulmonary epithelium of smokers and in non-small cell lung cancer, suggesting that it also plays a role in carcinogen-inflicted lung epithelial injury and carcinogenesis. We investigated the expression of PGP9.5 in mice in response to two prominent carcinogens found in tobacco smoke: Naphthalene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). By immunostaining, we found that PGP9.5 protein was highly expressed throughout the airway epithelium in the days immediately following a single injection of naphthalene. In contrast, PGP9.5 was exclusively confined to neurons and neuroendocrine cells in the control and NNK-exposed lungs. Furthermore, we investigated the expression of PGP9.5 mRNA in the lungs by quantitative RT-PCR (qPCR). PGP9.5 mRNA expression was highly upregulated in the days immediately following naphthalene injection and gradually returning to that of control mice 5 days after naphthalene injection. In contrast, exposure to NNK did not result in a significant increase in PGP9.5 mRNA 10 weeks after exposure. No increased expression of two other neuroendocrine markers was found in the non-neuroendocrine epithelial cells after naphthalene exposure. In contrast, immunostaining for the cell cycle regulator p27(Kip1), which has previously been associated with PGP9.5 in lung cancer cells, revealed transient downregulation of p27(Kip1) in naphthalene exposed airways compared to controls, indicating that the rise in PGP9.5 in the airway epithelium is related to downregulation of p27(Kip1). This study is the first to specifically identify the carcinogen naphthalene as an inducer of PGP9.5 expression in non-neuroendocrine epithelium after acute lung injury and further strengthens the accumulating evidence of PGP9.5 as a central player in lung epithelial damage and early carcinogenesis.
    Toxicology Letters 10/2008; 181(2):67-74. DOI:10.1016/j.toxlet.2008.06.872 · 3.36 Impact Factor
  • Journal of Thoracic Oncology 08/2007; 2(8). DOI:10.1097/01.JTO.0000283326.98730.cb · 5.80 Impact Factor
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    ABSTRACT: EGFRvIII is a mutant variant of the epidermal growth factor receptor (EGFR) found exclusively in various cancer types. EGFRvIII lacks a large part of the extracellular domain and is unable to bind ligands; however, the receptor is constitutively phosphorylated and able to activate downstream signaling pathways. Failure to attenuate signaling by receptor down-regulation could be one of the major mechanisms by which EGFRvIII becomes oncogenic. Using a cell system expressing either EGFR or EGFRvIII with no expression of other EGFR family members and with endogenous levels of key degradation proteins, we have investigated the down-regulation of EGFRvIII and compared it to that of EGFR. We show that, in contrast to EGFR, EGFRvIII is inefficiently degraded. EGFRvIII is internalized, but the internalization rate of the mutated receptor is significantly less than that of unstimulated EGFR. Moreover, internalized EGFRvIII is recycled rather than delivered to lysosomes. EGFRvIII binds the ubiquitin ligase c-Cbl via Grb2, whereas binding via phosphorylated tyrosine residue 1045 seems to be limited. Despite c-Cbl binding, the receptor fails to become effectively ubiquitinylated. Thus, our results suggest that the long lifetime of EGFRvIII is caused by inefficient internalization and impaired sorting to lysosomes due to lack of effective ubiquitinylation.
    Carcinogenesis 08/2007; 28(7):1408-17. DOI:10.1093/carcin/bgm058 · 5.27 Impact Factor
  • Journal of Thoracic Oncology 01/2007; 2. DOI:10.1097/01.JTO.0000283618.52252.2c · 5.80 Impact Factor
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    ABSTRACT: Small Cell Lung Cancer (SCLC) is an aggressive, highly metastatic disease for which there is currently no satisfactory treatment. Therefore development of novel treatment modalities is highly in demand. As SCLC is a disseminated disease, treatment must be administered systemically and therefore requires a high level of targeting. This can be achieved by transcriptionally targeted cancer gene therapy. We have identified promoters regions from several genes, which confer very high and SCLC specific mRNA expression - genes normally either only active during early developmental differentiation or associated with high proliferation.The insulinoma-associated 1 (INSM1) gene encodes a transcriptional repressor normally exclusively expressed transiently during early embryonic development in neuroendocrine regions, but has been found highly re-activated in neuroendocrine tumours, including SCLC. A 1.7 kb region of this promoter has very high activity in most SCLC cell lines and no activity in normal and other cancer cell lines. We have demonstrated that this promoter region confers sufficient activity when expressing a therapeutic gene to cause SCLC specific cell death in vitro and in vivo.The Achaete-Scute Homolog 1 (ASCL1) encoding a transcription factor transiently expressed during early development of neural and neuroendocrine progenitor cells, is also re-expressed in SCLC. A proximal 0.7 kb region of the ASCL1 promoter demonstrated high expression in a subset of SCLC cell lines with low or no expression in other cell lines. Addition of a suggested distal 2.5 kb repressor region gave no significant increase in specificity, but a general decrease in activity. The 0.7 kb promoter region regulating expression of a therapeutic gene was found to be sufficiently active to mediate SCLC specific cell death in vitro.The Enhancer of Zeste Homolog 2 (EZH2) gene is a member of the Polycomb group of proteins important for maintaining the silenced state of homeotic genes in the adult and is associated with high proliferation. EZH2 has been found highly overexpressed in a number of cancers, including SCLC. All tested cell lines (normal or cancer) have high expression of EZH2 mRNA, thus reflecting their high proliferative state. However, a 1.1 kb region of the EZH2 promoter displayed very high activity in SCLC cell lines, but not in other cell lines and was sufficiently active to mediate SCLC cell death in vitro. This short region of the EZH2 promoter has previously been shown to be activated by transcription factors from the E2F family. Preliminary results indicate that the high activity of the promoter region in SCLC is due to the lack of functional RB, which normally down regulates the activities of the E2F family. Therefore this short region of the promoter has potential for gene therapy for RB deficient cancers.The promoter regions from all three genes are currently being tested in mouse tumour models for activity and specificity using a novel liposomal delivery system for systemic application.
    Molecular Therapy 05/2006; 13. DOI:10.1016/j.ymthe.2006.08.385 · 6.43 Impact Factor
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    ABSTRACT: Cationic solid lipid nanoparticles (SLN) have recently been suggested for non-viral gene delivery, as these particles consist of well tolerated substances, can bind DNA directly via electrostatic interactions and mediate gene transfer in vitro. We here report the development of SLN complexes, which can be targeted to specific surface receptors. A formulation of SLN was prepared by the microemulsion technique comprising of stearylamine and the matrix lipid Compritol ATO 888 with a size of approximately 100 nm and a zeta-potential of +15. These SLN are able to condense DNA in complexes, which are very stable under physiological conditions, and they display low cytotoxicity in cell culture. In addition to binding of DNA, the SLN can simultaneously bind substantial amounts of streptavidin directly via electrostatic interactions. The SLN:DNA: streptavidin complexes are stable and are capable of binding biotinylated ligands, which can interact with surface receptors. This method allows for development of a fast and simple method of preparing a targeted non-viral gene therapy vector.
    European Journal of Pharmaceutics and Biopharmaceutics 03/2006; 62(2):155-62. DOI:10.1016/j.ejpb.2005.09.003 · 4.25 Impact Factor
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    ABSTRACT: Small cell lung cancer (SCLC) is a malignant disease, for which no satisfactory treatment is presently available and consequently, new specific therapeutic targets are in high demand. A global gene expression analysis previously performed, identified the neuronal pentraxin receptor (NPR) as highly and relatively specifically expressed in SCLC, consistent with the neuroendocrine features of this cancer. Normally, NPR is exclusively expressed in neurons, where it associates with the homologous proteins neuronal pentraxins 1 and 2 (NP1 and NP2) in complexes capable of binding the snake venom neurotoxin taipoxin. The purpose of the present study was to assess the toxic effect of taipoxin in SCLC-cell lines and to determine if toxicity correlates to NPR and NP1 and NP2 expression levels. NPR was detected by Western blot analysis in all the tested SCLC and in control cell lines of different origin. The receptor co-purified with cell membrane in SCLC, indicating that NPR is surface associated. Microarray signals for NP1 and NP2mRNA was detected in a subset of SCLC-cell lines and validated by Northern blot analysis. Furthermore, NP1 protein was detected by Western blot analysis in a few SCLC-cell lines, but not in the control cell lines. A number of SCLC-cell lines showed marked sensitivity to taipoxin (IC50: 3-130 nM) at toxin concentrations leaving the control cell lines unaffected. The sensitivity to taipoxin did not correlate with the expression levels of NP1 protein and NP2-mRNA, suggesting that expression of these proteins may not be required for taipoxin induced toxicity in SCLC. The demonstrated toxic effect of taipoxin in SCLC may prove to be of importance for designing novel specific treatment modalities for this disease.
    Lung Cancer 01/2006; 50(3):329-37. DOI:10.1016/j.lungcan.2005.06.011 · 3.74 Impact Factor
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    ABSTRACT: Overexpression or expression of activating mutations of the epidermal growth factor receptor (EGFR) is common in cancer and correlates with neoplastic progression. The present study employed Affymetrix oligonucleotide arrays to profile genes induced by ligand-activated EGFR with the receptor either moderately expressed or overexpressed at an in-itself transforming level. These changes were compared to those induced by the naturally occurring constitutively active variant EGFRvIII. This study provides novel insight on the activities and mechanisms of EGFRvIII and EGFR mediated transformation, as genes encoding proteins with functions in promoting cell proliferation, invasion, antiapoptosis, and angiogenesis featured prominently in the EGFRvIII- and EGFR-expressing cells. Surprisingly, it was found that ligand-activated EGFR induced the expression of a large group of genes known to be inducible by interferons. Expression of this module was absent in the EGFRvIII-expressing cell line and the parental cell line. Treatment with the specific EGFR inhibitor AG1478 indicated that the regulations were primary, receptor-mediated events. Furthermore, activation of this module correlated with activation of STAT1 and STAT3. The results thus demonstrate that ligand-activated EGFR at different expression levels results in different kinetics of signaling and induction of gene expression. In addition, the constitutively active variant EGFRvIII seems to activate only a subset of signal pathways and induce a subset of genes as compared to the ligand-activated EGFR.
    Journal of Cellular Biochemistry 10/2005; 96(2):412-27. DOI:10.1002/jcb.20554 · 3.37 Impact Factor

Publication Stats

451 Citations
157.67 Total Impact Points

Institutions

  • 2000–2014
    • Copenhagen University Hospital
      København, Capital Region, Denmark
  • 2012
    • Rigshospitalet
      København, Capital Region, Denmark
  • 2005–2010
    • National University (California)
      San Diego, California, United States
    • Louisiana State University Health Sciences Center New Orleans
      • Department of Pediatrics
      New Orleans, Louisiana, United States
  • 2007
    • Danish Cancer Society
      København, Capital Region, Denmark