DE19740384A1 - Antisense oligonucleotides specific for protein kinase C isoforms - Google Patents

Antisense oligonucleotides specific for protein kinase C isoforms

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Publication number
DE19740384A1
DE19740384A1 DE1997140384 DE19740384A DE19740384A1 DE 19740384 A1 DE19740384 A1 DE 19740384A1 DE 1997140384 DE1997140384 DE 1997140384 DE 19740384 A DE19740384 A DE 19740384A DE 19740384 A1 DE19740384 A1 DE 19740384A1
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Prior art keywords
antisense oligodeoxynucleotides
pkc
oligodeoxynucleotides according
antisense
isoform
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Application number
DE1997140384
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German (de)
Inventor
Hermann Prof Haller
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Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft
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Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft
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Priority to DE1997140384 priority Critical patent/DE19740384A1/en
Publication of DE19740384A1 publication Critical patent/DE19740384A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1137—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/315—Phosphorothioates

Abstract

Antisense DNA oligonucleotides specific for protein kinase C (PKC) isoforms are new.

Description

Die Erfindung betrifft spezifische Antisense Oligodesoxynukleotide (ODN) ge­ gen Proteinkinase C (PKC)-Isoformen zur Behebung und/oder Vermeidung von endothelialen Barrierendysfunktionen, insbesondere betrifft es Antisense Oligo­ desoxynukleotide, die gegen die 3' untranslatierte Region des PKC alpha-, delta-, epsilon- und zeta-Isoform gerichtet sind. Gegenstand der Erfindung sind fer­ nerhin die Verwendung dieser Antisense Oligodesoxynukleotide sowie pharma­ zeutische Zubereitungen, die diese Antisense Oligodesoxynukleotide enthalten.The invention relates to specific antisense oligodeoxynucleotides (ODN) protein kinase C (PKC) isoforms to correct and / or prevent endothelial barrier dysfunction, particularly affects antisense oligo deoxynucleotides that are alpha-, delta-, against the 3 'untranslated region of the PKC epsilon and zeta isoform are directed. The invention relates to fer nerhin the use of these antisense oligodeoxynucleotides and pharma preparations containing these antisense oligodeoxynucleotides.

Es ist bekannt, daß die Aktivierung des PKC-Systems durch Hyperglykämie ei­ ne wichtige Ursache sein kann, durch welche ungünstige Effekte bei Diabetes Erkrankungen initiiert werden (deRubertis FR und Craven PA Activation of protein kinase C in glomerular cells in diabetes. Mechanism and potential links to the pathogenesis of diabetic glomerulopathy. Diabetes 1994; 43: 1-8). Darüber hinaus ist beschrieben, daß eine PKC Aktivierung in endothelialen Zellen zu einer Verminderung in der endothelialen Zelldurchlässigkeit führt.It is known that the activation of the PKC system by hyperglycemia An important cause can be what adverse effects in diabetes Diseases are initiated (deRubertis FR and Craven PA Activation of protein kinase C in glomerular cells in diabetes. Mechanism and potential links to the pathogenesis of diabetic glomerulopathy. Diabetes 1994; 43: 1-8). About that In addition, PKC is described to activate in endothelial cells leads to a decrease in endothelial cell permeability.

PKC ist kein einzelnes Enzym, sondern es besteht aus verschiedenen eindeuti­ gen Isoformen, welche unterschiedliche enzymatische Eigenschaften und Funk­ tionen haben (Weinstein IB. The roles of specific isoforms of protein kinase C in groth control and human colon cancer. Princess Takamatsu Symp 1991; 22: 277-83).PKC is not a single enzyme, but consists of several distincti gene isoforms, which have different enzymatic properties and radio tion (Weinstein IB. The roles of specific isoforms of protein kinase C in groth control and human colon cancer. Princess Takamatsu Symp 1991; 22: 277-83).

Die bekannten Isoformen sind in drei große Familien in Abhängigkeit von ihren regulatorischen Eigenschaften eingeteilt. Die Isoformen der Gruppe I (α, βI, βII, γ) sind für ihre Aktivierung von Calcium und DAG (1,2-Diacyl-sn-glycerol) ab­ hängig. Gruppe II (δ-, ε-, θ-Isoformen) werden einzig und allein aktiviert durch DAG, während die Funktion der Isoformen der Gruppe III (ζ und λ) unabhängig von Calciumionen oder DAG für eine Aktivierung sind (Haller H, Lindschau C, Luft FC, Role of protein kinase C in intracellular signaling. Ann NY Acad. Sci 1994; 733: 313-324). The known isoforms are dependent on their in three large families regulatory properties. The group I isoforms (α, βI, βII, γ) are for their activation of calcium and DAG (1,2-diacyl-sn-glycerol) pending. Group II (δ, ε, θ isoforms) are only activated by DAG, while the function of the group III isoforms (ζ and λ) is independent of calcium ions or DAG for activation (Haller H, Lindschau C, Air FC, Role of protein kinase C in intracellular signaling. Ann NY Acad. Sci 1994; 733: 313-324).  

Unklar ist jedoch, welche der PKC-Isoformen durch hohe Glukosekonzentratio­ nen aktiviert werden und welche für die Übermittlung der zellulären Effekte der Hyperglykämie verantwortlich sind. Die Mechanismen der verminderten en­ dothelialen Zelldurchlässigkeit sind unklar.However, it is unclear which of the PKC isoforms due to high glucose concentration activated and which for the transmission of the cellular effects of Hyperglycaemia are responsible. The mechanisms of diminished dothelial cell permeability is unclear.

Der Erfindung lag die Aufgabe zugrunde, diese Mechanismen aufzuklären und und Substanzen für eine Therapie und/oder Prophylaxe zu finden.The object of the invention was to elucidate these mechanisms and and to find substances for therapy and / or prophylaxis.

Es wurde nunmehr gefunden, daß hohe extrazelluläre Glukosekonzentrationen zu einer rapiden dosis-unabhängigen Verminderung in der endothelialen Zell­ durchlässigkeit über eindeutig zuordenbare PKC-Isoformen führen. So handelt sich überraschend um die Isoformen α und ε, die eine Translocation durch hohe Glukosekonzentrationen erfahren. Der Effekt wurde durch Aktivierung von Pro­ teinkinase C in endothelialen Zellen vermittelt. Es wurden PKC-Isoformen α, δ, ε, ζ und θ aus Aorta-Endothelialzellen des Schweins identifiziert. Außerdem wurde festgestellt, daß sich der Phorbolester TPA (12-O-Tetradecanoyl-phorbol-13-ace­ tat), der als Aktivator von PKC bekannt ist und als "Tumor-Promotor" be­ zeichnet wird, weil er den Effekt von geringen Konzentrationen karzinogener Verbindungen erhöht, ähnlich dem Effekt der Glukose verhält und eine Vermin­ derung der Durchlässigkeit bewirkt.It has now been found that high extracellular glucose concentrations to a rapid dose-independent reduction in the endothelial cell permeability via clearly assignable PKC isoforms. So act is surprisingly about the isoforms α and ε, which translocation through high Experience glucose concentrations. The effect was achieved by activating Pro mediated kinkinase C in endothelial cells. PKC isoforms α, δ, ε, ζ and θ identified from porcine aortic endothelial cells. Furthermore it was found that the phorbol ester TPA (12-O-tetradecanoyl-phorbol-13-ace tat), which is known as an activator of PKC and as a "tumor promoter" is drawn because it has the effect of low carcinogenic concentrations Compounds increased, behaved similarly to the effect of glucose and a min changes in permeability.

Gemäß der Erfindung konnten nun Antisense Oligodesoxynukleotide (ODN) gegen PKC α bereitgestellt werden, die eine Expression der Isoform reduzieren, den Effekt der Glukose, nämlich endotheliale Barrierendysfunktionen, vollstän­ dig beseitigen und den TPA-Effekt signifikant verringern.According to the invention, antisense oligodeoxynucleotides (ODN) against PKC α, which reduce expression of the isoform, the effect of glucose, namely endothelial barrier dysfunction, completely Eliminate dig and significantly reduce the TPA effect.

Es handelt sich um Antisense ODN, die gegen die 3' untranslatierte Region des PKC alpha-Isoform gerichtet sind.It is an antisense ODN that acts against the 3 'untranslated region of the PKC alpha isoform are directed.

Bevorzugt handelt es sich um die Antisense ODN mit den folgenden Sequenzen (5'-3'), die als Phosphorothioat konditioniert vorliegen:
It is preferably the antisense ODN with the following sequences (5'-3 '), which are present conditioned as phosphorothioate:

  • a) CM-pan333a TCg CAg AAg gTg ggg (Größe 15mer)
    Zielsequenz: regulatorische Domäne (Position 333 HSPKCA)    a) CM-pan333a TCg CAg AAg gTg ggg (size 15mer)
    Target sequence: regulatory domain (position 333 HSPKCA)
  • b) CM-pan1502a ATC TCT ggg gCg ATA TAA TCT ggA g (25mer)
    Zielsequenz: enzymatische Domäne (Position 1502 HSPKCA1)    b) CM-pan1502a ATC TCT ggg gCg ATA TAA TCT ggA g (25mer)
    Target sequence: enzymatic domain (position 1502 HSPKCA1)
  • c) CM-pan343a TgC gAT CAC TgT ggg TCA gTG CTC T (25mer)
    Zielsequenz: enzymatische Domäne (Position 343 HSPKCA1)     c) CM-pan343a TgC gAT CAC TgT ggg TCA gTG CTC T (25mer)
    Target sequence: enzymatic domain (position 343 HSPKCA1)
  • d) ISIS 3527 gAg ACC CTg AAC AgT TgA TC (20mer)
    Zielsequenz: 3'-untranslatierter Abschnitt    d) ISIS 3527 gAg ACC CTg AAC AgT TgA TC (20mer)
    Target sequence: 3'-untranslated section
  • e) ISIS 3521 gTT CTC gCT ggT gAg TH CA (20mer)
    Zielsequenz: 3'-untranslatierter Abschnitt    e) ISIS 3521 gTT CTC gCT ggT gAg TH CA (20mer)
    Target sequence: 3'-untranslated section
  • f) ISIS 3522 AM ACg TCA gCC ATg gTC CC (20mer)
    Zielsequenz: ATG-Start-Codon    f) ISIS 3522 AM ACg TCA gCC ATg gTC CC (20mer)
    Target sequence: ATG start codon
  • g) MA-PKCA001 gTC AgC CAT ggT CCC (15mer)
    Zielsequenz: ATG-Start-Codon.    g) MA-PKCA001 gTC AgC CAT ggT CCC (15mer)
    Target sequence: ATG start codon.

Diese Antisense ODN werden gemäß der Erfindung bevorzugt zur Verhinderung und/oder Vermeidung endothelialer Barrierendysfunktionen, vorzugsweise ge­ gen durch hohe Glukosekonzentrationen induzierte Verminderungen der en­ dothelialen Zelldurchlässigkeit, eingesetzt. Damit sind sie insbesondere zur The­ rapie und/oder Prophylaxe von Organschäden durch Hyperglykämie, z. B. bei Diabetes mellitus geeignet.These antisense ODN are preferred according to the invention for prevention and / or avoidance of endothelial barrier dysfunctions, preferably ge gene induced by high glucose reductions dothelial cell permeability. This makes them especially for The Therapy and / or prophylaxis of organ damage due to hyperglycaemia, e.g. B. at Suitable for diabetes mellitus.

Darüber hinaus betrifft die Erfindung weitere Antisense ODN, so z. B. solche, die gegen die 3' untranslatierte Region des PKC, delta-, epsilon- und zeta-Isoform gerichtet sind.In addition, the invention relates to other antisense ODN, such. B. those who against the 3 'untranslated region of the PKC, delta, epsilon and zeta isoform are directed.

Ein erfindungsgemäßes Antisense ODN gegen PKC-delta weist die Sequenz
Tgg Agg ACg Tgg AH gCA AAC AgT C auf.
(CM-PKCD365-Größe 25mer).An antisense ODN according to the invention against PKC-delta has the sequence
Tgg Agg ACg Tgg AH gCA AAC AgT C on.
(CM-PKCD365 size 25mer).

Ein bevorzugtes Antisense ODN gegen die PKC epsilon-Isoform hat die Se­ quenz
gCC ATT gAA CAC TAC CAT.
(CM-PKC-E, Größe 18mer, Zielsequenz: ATG-Start-Codon).A preferred antisense ODN against the PKC epsilon isoform has the sequence
gCC ATT gAA CAC TAC CAT.
(CM-PKC-E, size 18mer, target sequence: ATG start codon).

Erfindungsgemäße Antisense ODN gegen PKC zeta-Isoform sind gekennzeich­ net durch die folgenden Sequenzen:
Antisense ODN according to the invention against PKC zeta isoform are characterized by the following sequences:

  • a) CM-PKCZ1756 gTc CAC gAC AgA gAC gCA CgC ggC C (25mer)
    Zielsequenz: 3'UTR (Position 1756)    a) CM-PKCZ1756 gTc CAC gAC AgA gAC gCA CgC ggC C (25mer)
    Target sequence: 3'UTR (position 1756)
  • b) CM-PKCZ595 gTA AgC AAT TCC ATC TgT CTC CTC g (25mer)
    Zielsequenz: V3-Domäne (Position 595)    b) CM-PKCZ595 gTA AgC AAT TCC ATC TgT CTC CTC g (25mer)
    Target sequence: V3 domain (position 595)
  • c) CM-PKCZ1954 gCA CAG CAg CAA gTT CCT CCA gCA C (25mer)
    Zielsequenz: 3'-UTR (Position 1954)     c) CM-PKCZ1954 gCA CAG CAg CAA gTT CCT CCA gCA C (25mer)
    Target sequence: 3'-UTR (position 1954)
  • d) CM-PKCZ001 gCC gCT CCC TTC CAT (15mer)
    Zielsequenz: Position 1-15 HSPKCZ.    d) CM-PKCZ001 gCC gCT CCC TTC CAT (15mer)
    Target sequence: Position 1-15 HSPKCZ.

Alle Antisense ODN liegen Phosphorothioat-konditioniert vor.All antisense ODN are phosphorothioate conditioned.

Die erfindungsgemäßen Antisense Oligodesoxynukleotide gegen die PKC al­ pha-, delta-, epsilon- und zeta-Isoform sind hervorragend gegen durch TPA indu­ zierte Verminderungen der endothelialen Zelldurchlässigkeit geeignet, insbe­ sondere sind die Antisense ODN gegen die PKC alpha- und epsilon-Isoform ge­ eignet.The antisense oligodeoxynucleotides according to the invention against the PKC al pha, delta, epsilon and zeta isoform are excellent against TPA indu graceful reductions in endothelial cell permeability suitable, esp the antisense ODN against the PKC alpha and epsilon isoform are special is suitable.

Gemäß der Erfindung werden sie zur Beeinflussung der Tumorangiogenese, insbesondere zur Inhibierung von Tumorwachstum verwendet.According to the invention, they are used to influence tumor angiogenesis, used in particular to inhibit tumor growth.

Die Erfindung betrifft auch pharmazeutische Zubereitungen, die ein oder mehre­ re Antisense Oligodesoxynukleotide umfassen und gegebenenfalls mit an sich üblichen Hilfs-, Träger- und Zusatzstoffen formuliert sind.The invention also relates to pharmaceutical preparations, one or more include antisense oligodeoxynucleotides and possibly with itself usual auxiliaries, carriers and additives are formulated.

Claims (14)

1. Spezifische Antisense Oligodesoxynukleotide (ODN) gegen Proteinkinase C (PKC)-Isoformen.1. Specific antisense oligodeoxynucleotides (ODN) against protein kinase C (PKC) isoforms. 2. Antisense Oligodesoxynukleotide nach Anspruch 1, dadurch gekennzeichnet, daß sie gegen die 3' untranslatierte Region der PKC alpha-Isoform ge­ richtet sind.2. Antisense oligodeoxynucleotides according to claim 1, characterized in that it was against the 3 'untranslated region of the PKC alpha isoform are aimed. 3. Antisense Oligodesoxynukleotide nach Anspruch 2, dadurch gekennzeichnet, daß sie die Sequenzen
TCg CAg AAg gTg ggg,
ATC TCT ggg gCg ATA TAA TCT ggA G,
TgC gAT CAC TgT ggg TCA gTg CTC T,
gAg ACC CTg AAC AgT TgA TC,
gTT CTC gCT ggT gAg TTT CA,
AAA ACg TCA gCC ATg gTC CC oder
gTC AgC CAT ggT CCC aufweisen.3. Antisense oligodeoxynucleotides according to claim 2, characterized in that they are the sequences
TCg CAg AAg gTg ggg,
ATC TCT ggg gCg ATA TAA TCT ggA G,
TgC gAT CAC TgT ggg TCA gTg CTC T,
gAg ACC CTg AAC AgT TgA TC,
gTT CTC gCT ggT gAg TTT CA,
AAA ACg TCA gCC ATg gTC CC or
gTC AgC CAT ggT CCC. 4. Antisense Oligodesoxynukleotide nach Anspruch 1, dadurch gekennzeichnet, daß sie gegen die 3' untranslatierte Region des PKC delta-Isoform ge­ richtet sind.4. Antisense oligodeoxynucleotides according to claim 1, characterized in that it is against the 3 'untranslated region of the PKC delta isoform are aimed. 5. Antisense Oligodesoxynukleotide nach Anspruch 4, dadurch gekennzeichnet, daß sie die Sequenz
Tgg Agg ACg Tgg ATT gCA AAC AgT C aufweisen.5. Antisense oligodeoxynucleotides according to claim 4, characterized in that they have the sequence
Tgg Agg ACg Tgg ATT gCA AAC AgT C. 6. Antisense Oligodesoxynukleotide nach Anspruch 1, dadurch gekennzeichnet, daß sie gegen die 3' untranslatierte Region des PKC epsilon-Isoform gerichtet sind. 6. Antisense oligodeoxynucleotides according to claim 1, characterized in that they are against the 3 'untranslated region of the PKC epsilon isoform are directed.   7. Antisense Oligodesoxynukleotide nach Anspruch 6, dadurch gekennzeichnet, daß sie die Sequenz
gCC ATT gAA CAC TAC CAT aufweisen.7. Antisense oligodeoxynucleotides according to claim 6, characterized in that they have the sequence
gCC ATT gAA CAC TAC CAT. 8. Antisense Oligodesoxynukleotide nach Anspruch 1, dadurch gekennzeichnet, daß sie gegen die 3' untranslatierte Region des PKC zeta-Isoform gerich­ tet sind.8. Antisense oligodeoxynucleotides according to claim 1, characterized in that it is directed against the 3 'untranslated region of the PKC zeta isoform are. 9. Antisense Oligodesoxynukleotide nach Anspruch 8, dadurch gekennzeichnet, daß sie die Sequenzen
gTc CAC gAC AgA gAC gCA CgC ggC C
gTA AgC AAT TCC ATC TgT CTC CTC g
gCA CAG CAg CAA gTT CCT CCA gCA C
gCC gCT CCC TTC CAT aufweisen.9. Antisense oligodeoxynucleotides according to claim 8, characterized in that they are the sequences
gTc CAC gAC AgA gAC gCA CgC ggC C
gTA AgC AAT TCC ATC TgT CTC CTC g
gCA CAG CAg CAA gTT CCT CCA gCA C
gCC gCT CCC TTC CAT. 10. Verwendung von Antisense Oligodesoxynukleotiden nach einem der Ansprüche 1 bis 3, zur Vermeidung und/oder Behebung von endothelialen Barrierendysfunktionen vorzugsweise gegen durch hohe Glukosekonzentrationen induzierte Verminderungen der endothelialen Zelldurchlässigkeit.10. Use of antisense oligodeoxynucleotides according to one of claims 1 to 3, to avoid and / or remedy of endothelial barrier dysfunctions, preferably against high ones Glucose concentrations induced decreases in endothelial Cell permeability. 11. Verwendung nach Anspruch 10, dadurch gekennzeichnet, daß sie zur Therapie und/oder Prophylaxe von Organschäden durch Hyper­ glykämie, z. B. bei Diabetes mellitus, eingesetzt werden.11. Use according to claim 10, characterized in that for the therapy and / or prophylaxis of organ damage caused by hyper glycemia, e.g. B. be used in diabetes mellitus. 12. Verwendung von Antisense Oligodesoxynukleotiden nach einem der Ansprüche 1 bis 9 gegen durch TPA induzierte endothelia­ le Barrierendysfunktionen.12. Use of antisense oligodeoxynucleotides according to one of claims 1 to 9 against TPA-induced endothelia le barrier dysfunctions. 13. Verwendung von Antisense Oligodesoxynukleotiden nach einem der Ansprüche 1 bis 9 zur Beeinflussung der Tumorangioge­ nese, insbesondere zur Inhibierung von Tumorwachstum. 13. Use of antisense oligodeoxynucleotides according to one of claims 1 to 9 for influencing the tumor angioge nese, especially for inhibiting tumor growth.   14. Pharmazeutische Zubereitungen umfassend ein oder mehrere Antisense Oligodesoxynukleotide nach einem der Ansprüche 1 bis 9, gegebenenfalls mit an sich üblichen Hilfs-, Träger- und Zusatzstoffen.14. Pharmaceutical preparations comprising one or more antisense Oligodeoxynucleotides according to one of claims 1 to 9, if appropriate with conventional auxiliary agents, carriers and additives.
DE1997140384 1997-09-08 1997-09-08 Antisense oligonucleotides specific for protein kinase C isoforms Withdrawn DE19740384A1 (en)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10244453A1 (en) * 2002-09-24 2004-04-01 Phenomiques Gmbh Inhibition of the protein kinase C-alpha for the treatment of diseases
WO2006094917A2 (en) * 2005-03-03 2006-09-14 Gentium Spa Oligodeoxyribonucleotides of 4000-10000 dalton for treating tumors
EP1867335A3 (en) * 2005-03-03 2008-03-12 Gentium S.p.A. Oligodeoxyribonucleotides combined with rapamycin for treating cancer
AU2007231651B2 (en) * 2005-03-03 2011-09-15 Gentium Spa Defibrotide and/or oligodeoxyribonucleotides for treating angiogenesis-dependent tumors
US8551967B2 (en) 2003-09-05 2013-10-08 Gentium Spa Formulations with anti-tumour action
US8785648B1 (en) 2010-08-10 2014-07-22 The Regents Of The University Of California PKC-epsilon inhibitors
US8980862B2 (en) 2010-11-12 2015-03-17 Gentium S.P.A. Defibrotide for use in prophylaxis and/or treatment of Graft versus Host Disease (GVHD)
WO2016003450A1 (en) 2014-07-01 2016-01-07 The Regents Of The University Of California Pkc-epsilon inhibitors
US9902952B2 (en) 2012-06-22 2018-02-27 Gentrum S.R.L. Euglobulin-based method for determining the biological activity of defibrotide
US10393731B2 (en) 2014-11-27 2019-08-27 Gentium S.R.L. Cellular-based method for determining the biological activity of defibrotide

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10244453A1 (en) * 2002-09-24 2004-04-01 Phenomiques Gmbh Inhibition of the protein kinase C-alpha for the treatment of diseases
WO2004028516A3 (en) * 2002-09-24 2004-11-11 Jan Menne Compositions for the inhibition of protein kinase c alpha for treatment of diabetes mellitus and cardiovascular diseases
EP2338498A1 (en) * 2002-09-24 2011-06-29 Phenos GmbH Compositions for the inhibition of protein kinase C alpha for the treatment of diabetes mellitus
AU2003280288B2 (en) * 2002-09-24 2008-08-28 Phenos Gmbh Compositions for the inhibition of protein kinase C alpha for treatment of diabetes mellitus and cardiovascular diseases
EA007926B1 (en) * 2002-09-24 2007-02-27 Фенос Гмбх Compositions for the inhibition of protein kinase c alpha for treatment of diabetes mellitus and cardiovascular diseases
US8551967B2 (en) 2003-09-05 2013-10-08 Gentium Spa Formulations with anti-tumour action
EP1867335A3 (en) * 2005-03-03 2008-03-12 Gentium S.p.A. Oligodeoxyribonucleotides combined with rapamycin for treating cancer
WO2006094917A3 (en) * 2005-03-03 2006-12-14 Gentium Spa Oligodeoxyribonucleotides of 4000-10000 dalton for treating tumors
WO2006094916A1 (en) * 2005-03-03 2006-09-14 Gentium Spa Defibrotide and/or oligodeoxyribonucleotides for treating angiogenesis-dependent tumors
AU2007231651B2 (en) * 2005-03-03 2011-09-15 Gentium Spa Defibrotide and/or oligodeoxyribonucleotides for treating angiogenesis-dependent tumors
AU2006222045B2 (en) * 2005-03-03 2011-10-20 Gentium Spa Oligodeoxyribonucleotides of 4000-10000 Dalton for treating tumors
WO2006094917A2 (en) * 2005-03-03 2006-09-14 Gentium Spa Oligodeoxyribonucleotides of 4000-10000 dalton for treating tumors
JP2008531647A (en) * 2005-03-03 2008-08-14 ゲンチウム エスピーエー Formulation with antitumor activity
US8785648B1 (en) 2010-08-10 2014-07-22 The Regents Of The University Of California PKC-epsilon inhibitors
US9376423B2 (en) 2010-08-10 2016-06-28 The Regents Of The University Of California PKC-epsilon inhibitors
US9867843B2 (en) 2010-11-12 2018-01-16 Gentium S.R.L. Defibrotide for use in prophylaxis and/or treatment of graft versus host disease (GVHD)
US8980862B2 (en) 2010-11-12 2015-03-17 Gentium S.P.A. Defibrotide for use in prophylaxis and/or treatment of Graft versus Host Disease (GVHD)
US9539277B2 (en) 2010-11-12 2017-01-10 Gentium S.R.L. Defibrotide for use in prophylaxis and/or treatment of graft versus host disease (GVHD)
US9902952B2 (en) 2012-06-22 2018-02-27 Gentrum S.R.L. Euglobulin-based method for determining the biological activity of defibrotide
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