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Evjen T.J.,Epitarget AS | Hupfeld S.,Clavis Pharma | Barnert S.,Albert Ludwigs University of Freiburg | Fossheim S.,Clavis Pharma | And 2 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2013

Ultrasound is investigated as a novel drug delivery tool within cancer therapy. Non-thermal ultrasound treatment of solid tumours post i.v.-injection of drug-carrying liposomes may induce local drug release from the carrier followed by enhanced intracellular drug uptake. Recently, ultrasound-mediated drug release of liposomes (sonosensitivity) was shown to strongly depend on liposome membrane composition. In the current study the ultrasound-mediated drug release mechanism of liposomes was investigated. The results showed that differences in ultrasound drug release kinetics obtained for different liposomal compositions were caused by distinctive release mechanisms of the carriers. Two types of liposomes composed of 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE) and hydrogenated soy l-α-phosphatidylcholine (HSPC) as main lipids, respectively, were recently shown to vary in sonosensitivity. Here, these liposomes were analyzed prior to and after a given ultrasound-exposure for their mean size, size distribution and morphology. Cryo-transmission electron microscopy, dynamic light scattering and asymmetric flow field-flow fractionation in combination with multi-angle light scattering revealed a significant change in mean size, size distribution and morphology of DOPE-based liposomes after ultrasound, pointing to an irreversible disruption of the vesicles and concomitant drug release. In contrast, the HSPC-based liposomes remained unchanged in size and structure after ultrasound application, indicating pore-mediated release mechanisms. The results show that the release mechanisms and interactions between ultrasound and liposomes depend on the liposome membrane-composition, explaining their sonosensitive properties. © 2013 Elsevier B.V.


Hummel-Eisenbeiss J.,German Cancer Research Center | Hascher A.,University of Munster | Hals P.-A.,Clavis Pharma | Sandvold M.L.,Clavis Pharma | And 3 more authors.
Molecular Pharmacology | Year: 2013

The nucleoside analog 5-azacytidine is an archetypical drug for epigenetic cancer therapy, and its clinical effectiveness has been demonstrated in the treatment of myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). However, therapy resistance in patients with MDS/AML remains a challenging issue. Membrane proteins that are involved in drug uptake are potential mediators of drug resistance. The responsible proteins for the transport of 5-azacytidine into MDS/AML cells are unknown. We have now systematically analyzed the expression and activity of various nucleoside transporters. We identified the human equilibrative nucleoside transporter 1 (hENT1) as the most abundant nucleoside transporter in leukemia cell lines and in AML patient samples. Transport assays using [14C]5-azacytidine demonstrated Na+-independent uptake of the drug into the cells, which was inhibited by S-(4- nitrobenzyl)-6-thioinosine (NBTI), a hENT1 inhibitor. The cellular toxicity of 5-azacytidine and its DNA demethylating activity were strongly reduced after hENT1 inhibition. In contrast, the cellular activity of the 5-azacytidine derivative 5-azacytidine- 5'-elaidate (CP-4200), a nucleoside transporter-independent drug, persisted after hENT1 inhibition. A strong dependence of 5-azacytidine-induced DNA demethylation on hENT1 activity was also confirmed by array-based DNA methylation profiling, which uncovered hundreds of loci that became demethylated only when hENT1-mediated transport was active. Our data establish hENT1 as a key transporter for the cellular uptake of 5-azacytidine in leukemia cells and raise the possibility that hENT1 expression might be a useful biomarker to predict the efficiency of 5-azacytidine treatments. Furthermore, our data suggest that CP-4200 may represent a valuable compound for the modulation of transporter-related 5-azacytidine resistances. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.


Brueckner B.,German Cancer Research Center | Rius M.,German Cancer Research Center | Markelova M.R.,Experimental Pharmacology and Oncology GmbH | Fichtner I.,Max Delbrück Center for Molecular Medicine | And 3 more authors.
Molecular Cancer Therapeutics | Year: 2010

Azacytidine is an established nucleoside drug that is well known for its ability to modulate epigenetic gene regulation by inhibition of DNA methylation. Despite recent advances in the clinical development of azacytidine, the use of the drug is limited by its low bioavailability and dependen cy on variably expressed nucleoside transporters for cellular uptake. We show here that CP-4200, an elaidic acid derivative of azacytidine, has strong epigenetic modulatory potency in human cancer cell lines, as evidenced by efficient depletion of DNA methyltransferase protein, genome-wide DNA demethylation, and robust reactivation of epigenetically silenced tumor suppressor genes. Importantly, however, the cellular uptake of CP-4200 was substantially less dependent on the nucleoside transporters that are known to be involved in azacytidine uptake. In agreement with this notion, CP-4200 showed a significantly higher antitumoral activity than azacytidine in an orthotopic mouse tumor model for acute lymphocytic leukemia. Together, these data represent a detailed characterization of the CP-4200 mode of action and suggest that elaidic acid modification improves the therapeutic efficacy of azacytidine.


Patent
Clavis Pharma | Date: 2010-11-15

The present invention relates to parenteral formulations for certain long chain saturated and monounsaturated fatty acid derivatives of 2,2-difluorodeoxycytidine (Gemcitabine). In particular, the present invention relates to a parenteral pharmaceutical composition and a method of the preparation thereof, in order to accommodate therapeutically effective doses of the said derivatives ameliorating compliance in treatment of cancer.


This invention provides methods and compositions for treating or otherwise ameliorating cancer in a subject, along with methods and compositions for measuring the levels of nucleoside transporters in a tumor and correlating this level to a predicated efficacy of a given anti-cancer drug regime, and methods and compositions for treating patients with low levels of hENT1 expression in cancer cells using a lipophilic gemcitabine analog such as gemcitabine-5-elaidate.


Patent
Clavis Pharma | Date: 2011-07-01

The present invention relates to parenteral formulations for certain long chain saturated and monounsaturated fatty acid derivatives of 1--D-arabinofuranosylcytosine (cytarabine). In particular, the present invention relates to a parenteral pharmaceutical composition and a method of the preparation thereof, in order to accommodate therapeutically effective doses of the said derivatives ameliorating compliance in treatment of cancer.


Trademark
Sharp Corporation and Clavis Pharma | Date: 2012-12-25

Pharmaceutical preparations for the prevention and treatment of cancer.


Trademark
Sharp Corporation and Clavis Pharma | Date: 2012-12-25

Pharmaceutical preparations for the prevention and treatment of cancer.


News Article | November 9, 2016
Site: www.newsmaker.com.au

Notes: Production, means the output of Acute Myeloid Leukemia (AML) Therapeutic Revenue, means the sales value of Acute Myeloid Leukemia (AML) Therapeutic This report studies Acute Myeloid Leukemia (AML) Therapeutic in Global market, especially in North America, Europe, China, Japan, Southeast Asia and India, focuses on top manufacturers in global market, with Production, price, revenue and market share for each manufacturer, covering Ambit Biosciences Inc. (US) Aprea AB (Sweden) Astellas Pharma Inc. (Japan) Astex Pharmaceuticals, Inc. (US) Bio-Path Holdings, Inc. (US) BioSante Pharmaceuticals, Inc. (US) Celator Pharmaceuticals, Inc. (US) Celgene Corp. (US) Clavis Pharma ASA (Norway) Cyclacel Pharmaceuticals, Inc. (US) EpiCept Corp. (US) Genzyme Corporation (US) Lorus Therapeutics, Inc. (Canada) Novartis AG (Switzerland) Onconova Therapeutics, Inc. (US) Market Segment by Regions, this report splits Global into several key Regions, with production, consumption, revenue, market share and growth rate of Acute Myeloid Leukemia (AML) Therapeutic in these regions, from 2011 to 2021 (forecast), like North America Europe China Japan Southeast Asia India Split by product type, with production, revenue, price, market share and growth rate of each type, can be divided into Type I Type II Type III Would like to place an order @ https://www.wiseguyreports.com/checkout?currency=one_user-USD&report_id=728047 Split by application, this report focuses on consumption, market share and growth rate of Acute Myeloid Leukemia (AML) Therapeutic in each application, can be divided into Application 1 Application 2 Application 3 Global Acute Myeloid Leukemia (AML) Therapeutic Market Research Report 2016 1 Acute Myeloid Leukemia (AML) Therapeutic Market Overview 1.1 Product Overview and Scope of Acute Myeloid Leukemia (AML) Therapeutic 1.2 Acute Myeloid Leukemia (AML) Therapeutic Segment by Type 1.2.1 Global Production Market Share of Acute Myeloid Leukemia (AML) Therapeutic by Type in 2015 1.2.2 Type I 1.2.3 Type II 1.2.4 Type III 1.3 Acute Myeloid Leukemia (AML) Therapeutic Segment by Application 1.3.1 Acute Myeloid Leukemia (AML) Therapeutic Consumption Market Share by Application in 2015 1.3.2 Application 1 1.3.3 Application 2 1.3.4 Application 3 1.4 Acute Myeloid Leukemia (AML) Therapeutic Market by Region 1.4.1 North America Status and Prospect (2011-2021) 1.4.2 Europe Status and Prospect (2011-2021) 1.4.3 China Status and Prospect (2011-2021) 1.4.4 Japan Status and Prospect (2011-2021) 1.4.5 Southeast Asia Status and Prospect (2011-2021) 1.4.6 India Status and Prospect (2011-2021) 1.5 Global Market Size (Value) of Acute Myeloid Leukemia (AML) Therapeutic (2011-2021) 2 Global Acute Myeloid Leukemia (AML) Therapeutic Market Competition by Manufacturers 2.1 Global Acute Myeloid Leukemia (AML) Therapeutic Production and Share by Manufacturers (2015 and 2016) 2.2 Global Acute Myeloid Leukemia (AML) Therapeutic Revenue and Share by Manufacturers (2015 and 2016) 2.3 Global Acute Myeloid Leukemia (AML) Therapeutic Average Price by Manufacturers (2015 and 2016) 2.4 Manufacturers Acute Myeloid Leukemia (AML) Therapeutic Manufacturing Base Distribution, Sales Area and Product Type 2.5 Acute Myeloid Leukemia (AML) Therapeutic Market Competitive Situation and Trends 2.5.1 Acute Myeloid Leukemia (AML) Therapeutic Market Concentration Rate 2.5.2 Acute Myeloid Leukemia (AML) Therapeutic Market Share of Top 3 and Top 5 Manufacturers 2.5.3 Mergers & Acquisitions, Expansion 3 Global Acute Myeloid Leukemia (AML) Therapeutic Production, Revenue (Value) by Region (2011-2016) 3.1 Global Acute Myeloid Leukemia (AML) Therapeutic Production and Market Share by Region (2011-2016) 3.2 Global Acute Myeloid Leukemia (AML) Therapeutic Revenue (Value) and Market Share by Region (2011-2016) 3.3 Global Acute Myeloid Leukemia (AML) Therapeutic Production, Revenue, Price and Gross Margin (2011-2016) 3.4 North America Acute Myeloid Leukemia (AML) Therapeutic Production, Revenue, Price and Gross Margin (2011-2016) 3.5 Europe Acute Myeloid Leukemia (AML) Therapeutic Production, Revenue, Price and Gross Margin (2011-2016) 3.6 China Acute Myeloid Leukemia (AML) Therapeutic Production, Revenue, Price and Gross Margin (2011-2016) 3.7 Japan Acute Myeloid Leukemia (AML) Therapeutic Production, Revenue, Price and Gross Margin (2011-2016) 3.8 Southeast Asia Acute Myeloid Leukemia (AML) Therapeutic Production, Revenue, Price and Gross Margin (2011-2016) 3.9 India Acute Myeloid Leukemia (AML) Therapeutic Production, Revenue, Price and Gross Margin (2011-2016) 4 Global Acute Myeloid Leukemia (AML) Therapeutic Supply (Production), Consumption, Export, Import by Regions (2011-2016) 4.1 Global Acute Myeloid Leukemia (AML) Therapeutic Consumption by Regions (2011-2016) 4.2 North America Acute Myeloid Leukemia (AML) Therapeutic Production, Consumption, Export, Import by Regions (2011-2016) 4.3 Europe Acute Myeloid Leukemia (AML) Therapeutic Production, Consumption, Export, Import by Regions (2011-2016) 4.4 China Acute Myeloid Leukemia (AML) Therapeutic Production, Consumption, Export, Import by Regions (2011-2016) 4.5 Japan Acute Myeloid Leukemia (AML) Therapeutic Production, Consumption, Export, Import by Regions (2011-2016) 4.6 Southeast Asia Acute Myeloid Leukemia (AML) Therapeutic Production, Consumption, Export, Import by Regions (2011-2016) 4.7 India Acute Myeloid Leukemia (AML) Therapeutic Production, Consumption, Export, Import by Regions (2011-2016) 5 Global Acute Myeloid Leukemia (AML) Therapeutic Production, Revenue (Value), Price Trend by Type 5.1 Global Acute Myeloid Leukemia (AML) Therapeutic Production and Market Share by Type (2011-2016) 5.2 Global Acute Myeloid Leukemia (AML) Therapeutic Revenue and Market Share by Type (2011-2016) 5.3 Global Acute Myeloid Leukemia (AML) Therapeutic Price by Type (2011-2016) 5.4 Global Acute Myeloid Leukemia (AML) Therapeutic Production Growth by Type (2011-2016)


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