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  • Springer (CrossRef)  (9)
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  • 1
    Language: English
    In: European Journal of Nuclear Medicine and Molecular Imaging, 2012, Vol.39(1), pp.149-159
    Description: Byline: Thomas Wanek (1), Claudia Kuntner (1), Jens P. Bankstahl (2), Marion Bankstahl (2), Johann Stanek (1,3), Michael Sauberer (1), Severin Mairinger (1,3,4), Sabine Strommer (3), Volker Wacheck (3), Wolfgang Loscher (2), Thomas Erker (4), Markus Muller (3), Oliver Langer (1,3) Keywords: Multidrug resistance; P-glycoprotein; Positron emission tomography; [[.sup.11]C]Tariquidar; [[.sup.11]C]Elacridar; (R)[-[.sup.11]C]Verapamil Abstract: Purpose One important mechanism for chemoresistance of tumours is overexpression of the adenosine triphosphate-binding cassette transporter P-glycoprotein (Pgp). Pgp reduces intracellular concentrations of chemotherapeutic drugs. The aim of this study was to compare the suitability of the radiolabelled Pgp inhibitors [[.sup.11]C]tariquidar and [[.sup.11]C]elacridar with the Pgp substrate radiotracer (R)[-[.sup.11]C]verapamil for discriminating tumours expressing low and high levels of Pgp using small-animal PET imaging in a murine breast cancer model. Methods Murine mammary carcinoma cells (EMT6) were continuously exposed to doxorubicin to generate a Pgp-overexpressing, doxorubicin-resistant cell line (EMT6AR1.0 cells). Both cell lines were subcutaneously injected into female athymic nude mice. One week after implantation, animals underwent PET scans with [[.sup.11]C]tariquidar (n=7), [[.sup.11]C]elacridar (n=6) and (R)[-[.sup.11]C]verapamil (n=7), before and after administration of unlabelled tariquidar (15 mg/kg). Pgp expression in tumour grafts was evaluated by Western blotting. Results [11C]Tariquidar showed significantly higher retention in Pgp-overexpressing EMT6AR1.0 compared with EMT6 tumours: the mean+-SD areas under the time--activity curves in scan 1 from time 0 to 60 min (AUC.sub.0--60) were 38.8+-2.2 min and 25.0+-5.3 min (p=0.016, Wilcoxon matched pairs test). [[.sup.11]C]Elacridar and (R)[-[.sup.11]C]verapamil were not able to discriminate Pgp expression in tumour models. Following administration of unlabelled tariquidar, both EMT6Ar1.0 and EMT6 tumours showed increases in uptake of [[.sup.11]C]tariquidar, [[.sup.11]C]elacridar and (R)[-[.sup.11]C]verapamil. Conclusion Among the tested radiotracers, [[.sup.11]C]tariquidar performed best in discriminating tumours expressing high and low levels of Pgp. Therefore [[.sup.11]C]tariquidar merits further investigation as a PET tracer to assess Pgp expression levels in solid tumours. Author Affiliation: (1) Health & Environment Department, Molecular Medicine, AIT Austrian Institute of Technology GmbH, 2444, Seibersdorf, Austria (2) Department of Pharmacology, Toxicology & Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany (3) Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria (4) Department of Medicinal Chemistry, University of Vienna, Vienna, Austria Article History: Registration Date: 09/09/2011 Received Date: 24/05/2011 Accepted Date: 09/09/2011 Online Date: 08/10/2011 Article note: Electronic supplementary material The online version of this article (doi: 10.1007/s00259-011-1941-7) contains supplementary material, which is available to authorized users.
    Keywords: Multidrug resistance ; P-glycoprotein ; Positron emission tomography ; [C]Tariquidar ; [C]Elacridar ; ()-[C]Verapamil
    ISSN: 1619-7070
    E-ISSN: 1619-7089
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  • 2
    Language: English
    In: Investigational New Drugs, 2016, Vol.34(5), pp.584-595
    Description: Background MET is a tyrosine kinase receptor involved in the regulation of cell proliferation and migration. Reported here are the phase I dose-escalation results for LY2875358, a monoclonal antibody against MET, in Japanese patients with advanced malignancies. Methods The study comprised a 3 + 3 dose-escalation part for LY2875358 monotherapy in patients with advanced malignancies (Part A) followed by an assessment of LY2875358 in combination with erlotinib or gefitinib in patients with non-small cell lung cancer (Part B). LY2875358 was administered once every 2 weeks. The primary objective was to evaluate the safety and tolerability of LY2875358; secondary objectives included evaluation of pharmacokinetics, pharmacodynamics, and antitumor activity. Results Eleven patients received LY2875358 monotherapy at 3 dose levels (700 mg, N  = 3; 1400 mg, N  = 3; 2000 mg, N  = 5) and 6 patients received LY2875358 2000 mg in combination with erlotinib ( N  = 3) or gefitinib ( N  = 3). No dose-limiting toxicities or serious adverse events related to LY2875358 were observed. The most frequently reported drug-related adverse events were hypoalbuminemia (2 patients) in Part A and dermatitis acneiform (4 patients) in Part B. LY2875358 area under the curve (AUC) and maximum concentration (C max ) increased with dose over the dose range of 700 mg to 2000 mg. A best response of stable disease was achieved by 2/11 patients in Part A and 4/6 patients in Part B (disease control rate: 35 %). Conclusions LY2875358 at doses up to 2000 mg demonstrated a favorable safety and tolerability profile as monotherapy or in combination with erlotinib or gefitinib in Japanese patients with advanced malignancies.
    Keywords: Antibodies, monoclonal ; Epidermal growth factor receptor ; LY2875358 ; MET ; Pharmacokinetics ; Solid tumors
    ISSN: 0167-6997
    E-ISSN: 1573-0646
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  • 3
    Language: German
    In: Wiener Medizinische Wochenschrift, 2006, Vol.156(17), pp.481-487
    Description: Oligonucleotide therapeutics are short, single- or double-stranded DNA or RNA molecules consisting of strands of 10–50 nucleotides. By targeted modulation of gene expression oligonucleotides provide the chance of targeting diseases at their molecular level. Within this novel emerging class of compounds oligonucleotide therapeutics are discriminated by their structure, function and mode of action. While antisense oligonucleotides, ribozymes and siRNAs suppress the expression of a protein by complementary hybridizing with their target mRNA, aptamers bind like antibodies to their target protein and thereby inhibit its function. Immunostimulatory oligonucleotides are due to sequence motifs within their nucleotide sequence able to trigger a therapeutic exploitable immune response. Currently, there are only two oligonucleotide therapeutics approved by the FDA, namely the antisense oligonucleotide Fomivirsen and the aptamer Macugen. In this review the mode of action of the diverse oligonucleotide therapeutics and their current status in clinical development will be discussed. Oligonukleotid Therapeutika sind kurzkettige DNA oder RNA Moleküle, die aus Einzeloder Doppelsträngen von 10–50 Nukleotiden bestehen. Sie ermöglichen gezielt die Expression von Genen zu beeinflussen, um Erkrankungen auf ihrer molekularen Ebene der Entstehung zu therapieren. Innerhalb dieser neuen Substanzklasse unterscheidet man je nach Struktur, Wirkungs- und Funktionsweise zwischen Antisense Oligonukleotiden, Ribozymen, siRNAs, Aptameren und immunstimulatorischen Oligonukleotiden. Während Antisense Oligonukleotide, Ribozyme und siRNAs gezielt die Expression eines Proteins durch komplementäre Basenpaarung an ihre Ziel-mRNA unterdrücken, binden Aptamere ähnlich wie Antikörper spezifisch an ihr Zielprotein und hemmen damit dessen Funktion. Immunstimulatorische Oligonukleotide sind aufgrund bestimmter in ihrer Nukleotidsequenz enthaltener "Sequenzmotive" in der Lage eine therapeutisch nutzbare Immunreaktion hervorzurufen. Derzeit sind mit dem Antisense Oligonukleotid Fomivirsen und dem Aptamer Macugen zwei Oligonukleotide als Arzneimittel zugelassen. Im vorliegenden Artikel sollen die Wirkungsmechanismen der unterschiedlichen Oligonukleotide dargestellt und eine Übersicht über den derzeitigen Entwicklungsstand als Therapeutika in den unterschiedlichen Indikationsbereichen gegeben werden.
    Keywords: Oligonucleotide therapeutics ; Antisene ; siRNA ; Aptamer ; CpG
    ISSN: 0043-5341
    E-ISSN: 1563-258X
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  • 4
    Language: English
    In: Investigational New Drugs, 2018, Vol.36(4), pp.536-544
    Description: Purpose Approximately 3% of lung cancer bears mutations leading to MET exon 14 skipping, an oncogenic driver which is further evidenced by case reports of patient response to MET kinase inhibitor treatment. Approximately 15% of tumors harboring MET exon14 skipping have concurrent MET amplification. Experimental Design Merestinib is a type II MET kinase inhibitor. Emibetuzumab, a bivalent anti-MET antibody, internalizes MET receptor. Each single agent and the combination were evaluated in the Hs746t gastric cancer line bearing MET exon14 skipping and MET amplification. Results Merestinib inhibited Hs746t cell proliferation (IC 50 =34 nM) and totally eliminated pMET at 100nM. Emibetuzumab showed little anti-proliferative activity against Hs746t cells (IC 50 〉100nM), did not reduce pMET, and slightly reduced cell surface MET. In the Hs746t xenograft model, dose dependent differences in durability of response were seen with merestinib including durable tumor regression (91.8%) at 12 mg/kg qd. Emibetuzumab treatment (10mg/kg qw) provided transient tumor regression (37.7%), but tumors re-grew while on treatment. Concurrent combination of merestinib (6 mg/kg qd) and emibetuzumab resulted in 85% tumor regression, while a sequential combination (initiating merestinib first) resulted in longer duration of treatment response. Conclusions Data in this study support a clinical evaluation of merestinib in patients with MET exon 14 skipping (NCT02920996). As a type II MET kinase inhibitor, merestinib may provide a therapeutic option to treatment naïve patients or to patients who progress on type I MET inhibitor treatment. Data also support clinical evaluation of the sequential combination of merestinib with emibetuzumab when patients progress on single agent merestinib.
    Keywords: Merestinib ; Emibetuzumab ; MET exon 14 skipping ; MET kinase inhibitor ; MET antibody ; LY2801653 ; LY2875358
    ISSN: 0167-6997
    E-ISSN: 1573-0646
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  • 5
    Language: English
    In: Cancer Chemotherapy and Pharmacology, 2017, Vol.80(6), pp.1197-1207
    Description: To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1007/s00280-017-3445-z Byline: Daisuke Sakai (1), Hyun Cheol Chung (2), Do-Youn Oh (3,4), Se Hoon Park (5), Shigenori Kadowaki (6), Yeul Hong Kim (7), Akihito Tsuji (8), Yoshito Komatsu (9), Yoon-Koo Kang (10), Kazunori Uenaka (11), Sameera R. Wijayawardana (12), Volker Wacheck (12), Xuejing Wang (12), Ayuko Yamamura (11), Toshihiko Doi (13) Keywords: Antibodies, monoclonal, humanized; Clinical trial; Phase II; LY2875358; MET protein, human; Stomach neoplasms Abstract: Purpose Mesenchymal--epithelial transition factor (MET) is expressed in gastric cancer and associated with poor clinical outcomes. We assessed activity, safety, and pharmacokinetics of emibetuzumab, a bivalent monoclonal anti-MET antibody that blocks ligand-dependent and ligand-independent MET signaling. Methods This non-randomized, single-arm, Phase 2 study enrolled Asian patients with MET diagnostic positive advanced gastric adenocarcinoma. Emibetuzumab (2000 mg, intravenous) was given on days 1 and 15 (28-day cycle). The primary endpoint was 8-week progression-free survival rate. Secondary objectives included safety, pharmacokinetics, overall survival, and change in tumor size. Results Tumors from 65 patients were immunohistochemically screened to enroll 15 MET diagnostic positive patients (23% positivity 8 Japanese, 7 Korean 10 male). Eight-week progression-free survival rate was 0.47 (70% CI, 0.33--0.59). Disease control rate was 40% (target lesion decreases, three patients no complete/partial responses according to RECIST). Median overall survival was 17.1 weeks (95% CI, 6.3--not achievable). No serious emibetuzumab-related adverse events or new safety signals emerged. GradeAaAaAeAc[yen]3 possibly drug-related adverse events were hyperkalemi hyponatremia, and hyperuricemia (one each). Emibetuzumab's pharmacokinetics profile was similar to that observed previously. MET expression and clinical outcomes were not obviously associated. Conclusion Emibetuzumab was well tolerated with limited single-agent activity in advanced gastric adenocarcinoma. Author Affiliation: (1) Osaka University Hospital, Osaka, 565-0871, Japan (2) Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, 03722, South Korea (3) Seoul National University Hospital, Seoul, 03080, South Korea (4) Cancer Research Institute, Seoul National University College of Medicine, Seoul, 03080, South Korea (5) Sungkyunkwan University Samsung Medical Center, Seoul, 06351, South Korea (6) Aichi Cancer Center Hospital, Nagoya, 464-8681, Japan (7) Korea University College of Medicine, Seoul, 02841, South Korea (8) Department of Clinical Oncology, Faculty of Medicine, Kagawa University, Kita, 761-0793, Japan (9) Cancer Center, Hokkaido University Hospital, Sapporo, 060-8648, Japan (10) Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736, South Korea (11) Eli Lilly Japan K.K., Kobe, 651-0086, Japan (12) Eli Lilly and Company, Indianapolis, IN, 46285, USA (13) National Cancer Center Hospital East, 5-1, Kashiwanoha 6-chome, Kashiwa, Chiba, 277-8577, Japan Article History: Registration Date: 23/09/2017 Received Date: 05/09/2017 Accepted Date: 22/09/2017 Online Date: 25/10/2017
    Keywords: Antibodies, monoclonal, humanized ; Clinical trial ; Phase II ; LY2875358 ; MET protein, human ; Stomach neoplasms
    ISSN: 0344-5704
    E-ISSN: 1432-0843
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  • 6
    Language: English
    In: Monatshefte für Chemie - Chemical Monthly, 2008, Vol.139(5), pp.575-578
    Description: In continuation of our studies on compounds with a resveratrol-based scaffold two compounds with N -containing functional groups have been synthesized and screened for their inhibitory effect on the growth of the human cancer cell lines HT29, 518A2, AsPC-1, BxPC-3, and PC-3. Compound 4 , but not 1 , demonstrated pronounced in vitro cytotoxicity against all these cancer cell lines, thus making this compound a promising candidate for further preclinical in vivo studies.
    Keywords: Antitumor agents; Amidoximes; Resveratrol; Drug research.
    ISSN: 0026-9247
    E-ISSN: 1434-4475
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  • 7
    Language: English
    In: Molecular medicine (Cambridge, Mass.), December 2002, Vol.8(12), pp.877-84
    Description: Currently there is no information on the regulation of expression and physiological role of the anti-apoptotic protein Mcl-1 in cells of the melanocytic lineage. This study investigates the regulation and expression of Mcl-1 in human melanoma cells, which was recently found to be induced by betulinic acid, a compound with anti-melanoma and apoptosis-inducing potential. Mcl-1 phosphorthioate antisense oligonucleotides were used to investigate the effect of downregulating the expression of Mcl-1. Regulation of Mcl-1 expression was analyzed with the specific PI3-kinase inhibitors LY294002 and wortmannin and the inhibitor of MAP-kinase activation, PD98059. Western blot analysis was performed with anti ERK1/2, Mcl-1, Bak, Bcl-x and Bax antibodies. Activation status of PI-3 kinase and MAP-kinase pathways was investigated using phospho-Akt and phosphorylation-state independent Akt as well as phospho-MAP kinase, phospho-MEK and phospho-GSK-3alpha/beta antibodies. Upregulation of Mcl-1 in human melanoma cells by betulinic acid is mediated via a signal-transduction pathway that is inhibited by LY294002 and wortmannin. Betulinic acid-induced phosphorylation and activation of the Akt protein kinase was inhibited by LY294002. The inhibitor PD98059 reduced expression levels of Mcl-1 in melanoma cells and this effect was counteracted by betulinic acid. Downregulation of Mcl-1 by antisense oligodeoxynucleotides in combination with betulinic treatment led to a synergistic effect regarding growth inhibition. These results suggest that in human melanoma cells Mcl-1 is (i) of functional relevance for survival and (ii) subject to dual regulation by the MAP- kinase pathway and a pathway involving protein kinase B/Akt, the latter of which is modulated in response to betulinic acid. This study provides an experimental foundation for future therapeutic strategies using anti-Mcl-1 antisense oligonucleotides in human melanoma.
    Keywords: Protein-Serine-Threonine Kinases ; Melanoma -- Metabolism ; Neoplasm Proteins -- Genetics ; Triterpenes -- Metabolism
    ISSN: 1076-1551
    E-ISSN: 15283658
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  • 8
    Language: English
    In: Journal of Molecular Medicine, 2001, Vol.79(10), pp.587-593
    Description: We used Bcl-2 antisense oligonucleotides (G3139) to chemosensitize human gastric cancer by downregulation of Bcl-2 expression in vivo. Oligonucleotides and cisplatin were administered systemically in a human gastric cancer SCID mouse model, and Bcl-2 expression, apoptosis, tumor size, and survival were assessed. Used alone, G3139 treatment led to downregulation of Bcl-2 and moderate tumor reduction compared to saline control. G3139 combined with cisplatin treatment markedly enhanced the antitumor effect of cisplatin (70% tumor size reduction vs. cisplatin alone), associated with increased apoptosis measured in tumor biopsy specimens. Combined treatment with G3139 and cisplatin prolonged survival of the tumor-bearing SCID mice by more than 50% without adding significant drug-related toxicity. Treatment with Bcl-2 antisense oligonucleotides is thus a promising novel approach to enhance antitumor activity of cisplatin or other drugs used in gastric cancer therapy and warrants further evaluation in clinical trials.
    Keywords: Gastric cancer Antisense oligonucleotides Bcl-2 Chemoresistance Apoptosis
    ISSN: 0946-2716
    E-ISSN: 1432-1440
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  • 9
    Language: English
    In: Molecular Medicine, 8/2000, Vol.6(8), pp.693-704
    Description: BACKGROUND: In colon cancer, K-Ras oncogenes, which appear to be linked to chemoresistance and poor prognosis, are activated in more than 50% of cases, whereas the tumor suppressor gene p53 is mutationally altered in about 70% of all cases. The transcription factor p53, which is frequently mutated at codon 273, maintains wild-type configuration and possibly carries out residual functions. Although blocking of activated K-Ras may constitute a rational therapeutic concept for this treatment-resistant malignancy, a strategy influencing both oncogenic Ras and the tumor suppressor p53 may be even more promising.MATERIALS AND METHODS: We evaluated the effects of S-trans, trans-farnesyl-thiosalicylic acid (FTS), a novel Ras antagonist on human SW480 and HT-29 colon cancer cells, which both harbor a p53 His273 mutation but express activated K-Ras and wild-type, but overexpressed, H-Ras, respectively. Besides cell growth and morphology, levels of cellular Ras proteins, regulation of p53 and p21(waf1/cip1) expression were analyzed by immunoblotting. The cell cycle arresting potential of FTS was quantified by flow cytometry.RESULTS: We demonstrate that FTS treatment alters the morphology and blocks the growth of SW480 and HT-29 colon cancer cells by both reducing the total amount of Ras and up-regulating the tumor suppressor p53. Furthermore, FTS caused an upregulation of the cyclin-cyclin-dependent kinase (CDK) inhibitor p21(waf1/cip1) and blocked the cell cycle. p53 antisense oligonucleotides not only reduced the level of p53 proteins but correspondingly also blocked the expression of p21(waf1/cip1) in FTS-treated colon cancer cells.CONCLUSIONS: FTS, a unique compound capable of regulating both oncogenic Ras and the tumor suppressor p53 may prove particularly useful for the therapy of colon cancer and other treatment-resistant malignancies where Ras is altered and p53 is either wild-type or mutated in positions that allow residual p53 functions.
    Keywords: Biology;
    ISSN: 1076-1551
    E-ISSN: 1528-3658
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