WO2004003564A2 - Marqueurs tumoraux et leur utilisation aux fins de diagnostic et traitement de maladies tumorales - Google Patents

Marqueurs tumoraux et leur utilisation aux fins de diagnostic et traitement de maladies tumorales Download PDF

Info

Publication number
WO2004003564A2
WO2004003564A2 PCT/EP2003/006748 EP0306748W WO2004003564A2 WO 2004003564 A2 WO2004003564 A2 WO 2004003564A2 EP 0306748 W EP0306748 W EP 0306748W WO 2004003564 A2 WO2004003564 A2 WO 2004003564A2
Authority
WO
WIPO (PCT)
Prior art keywords
protein
proteins
level
spots
tumor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2003/006748
Other languages
German (de)
English (en)
Other versions
WO2004003564A3 (fr
Inventor
Stephanie Lamer
Marie-Laure Fogeron
Hermann Lage
Udo Kellner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
EUROPROTEOME AG
Original Assignee
EUROPROTEOME AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by EUROPROTEOME AG filed Critical EUROPROTEOME AG
Priority to AU2003246592A priority Critical patent/AU2003246592A1/en
Publication of WO2004003564A2 publication Critical patent/WO2004003564A2/fr
Anticipated expiration legal-status Critical
Publication of WO2004003564A3 publication Critical patent/WO2004003564A3/fr
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • C07K1/24—Extraction; Separation; Purification by electrochemical means
    • C07K1/26—Electrophoresis
    • C07K1/28—Isoelectric focusing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to the use of markers for the detection of tumors and for the therapy of tumor diseases.
  • the following proteins could be identified as a means for cancer risk assessment, diagnosis and therapy of tumors or carcinomas: Type II membrane protein NP 055070 (each Swiss Prot.
  • NHP2-like protein 1 P55769 pre-mRNA cleavage factor Im (25kD) NP008937, lysyl-tRNA synthetase Q15046, UNR-interacting protein Q9Y3F4, nuclear transport factor 2 P13662, erytrocyte phosphatase isoenzyme F P24666, prefoldin subunit 2 Q9UHV9, heterogeneous nuclear ribonucleofluidic acid p2, p2-oligonucleotide protein-C1, p2-oligonucleotide protein-C1, p2-oligonucleotide protein-C1, p2-oligonucleotide protein-C1, p2-oligonucleotide-C1, p2-oligonucleotide-C1-P3 P13995, 47 kDa heat shock protein precursor P29043, ubiquinol-cytochrome C reductase complex core protein P31930, its fragments, recognition substances directed against these and /
  • a tumor is a locally defined increase in tissue volume, although in the broader sense any localized swelling due to edema, acute or chronic inflammation or the like can be referred to as a tumor.
  • tissue formations such as blastoma or neoplasia, are understood in the form of spontaneous, differently uninhibited, autonomous and irreversible excess growth of the body's own tissue as a tumor, whereby the tumor growth is associated with a loss of specific cell and tissue functions can according to her biological behavior, according to a histogenetic system or according to clinical and pathological findings.
  • tumor markers are either produced by the tumor tissue itself or as a reaction of the body to the tumor.
  • tumor markers also refer to cellular changes, the qualitative or quantitative analysis of which enables a statement to be made about the presence, the course or a prognosis of malignant diseases.
  • Tumor markers are usually physiologically occurring substances that can be detected in increased or decreased concentrations compared to physiological conditions in serum, urine or other body fluids, whereby these substances are synthesized and secreted in the tumor tissue and released by tumor decay or formed as a reaction of the organism to a tumor.
  • PSA prostate-specific antigen
  • prostatic acid phosphatase occur in prostate carcinomas.
  • Alpha tetoprotein is a protein that is normally produced by the fetus. If it is found in the blood of non-pregnant women or men, it indicates a liver or germline tumor. Lactate dehydrogenase (LDH) is an important enzyme in the human body and is found in almost every tissue.
  • a greatly increased level of LDH in the blood can be caused by forms of cancer such as leukemia.
  • cancer such as leukemia.
  • p53 autoantibodies which are indicative transformed cells can be detected.
  • Cellular tumor markers are, for example, hormone receptors, receptors for growth-promoting substances in leukemia and cell markers, which indicate an increased expression of 5 oncogenic genes and monoclonal cell growth.
  • a disadvantage of the known methods for the detection of tumors is that all methods, regardless of whether the doctor e.g. the prostate carcinoma by palpation
  • Tumor diagnostics including the use of tumor markers cannot be determined.
  • tumor markers can also appear in non-carcinogenic diseases; continues to mean a
  • a further disadvantage is that the known means and methods cannot be used to determine whether a tissue that is currently still healthy and unremarkable can degenerate at a later point in time, that is to say whether it tends to develop from
  • the object of the invention was therefore to provide means and methods for tumor diagnosis and therapy which do not have the disadvantages mentioned and in particular allow simple, safe and inexpensive detection or therapy of tumor diseases.
  • the present invention solves this technical problem by using type II membrane protein NP 055070 (Swiss-Prot. Number), NHP2-like protein 1 P55769, pre-mRNA cleavage factor Im (25kD) NP008937, lysyl-tRNA synthetase Q15046, UNR -interagierendes protein Q9Y3F4, nuclear transport factor 2 P13662, Erytrozytenphosphatasel isoenzymes F P24666, Prefoldin subunit 2 Q9UHV9, heterogeneous nuclear ribonucleoprotein C1 / C2 P07910, transitionale endoplasmic reticulum ATPase P55072, bifunctional Methylenetetrahydrofolklare dehydrogenase P13995, 47 kDa heat shock protein precursor P29043, ubiquinol-cytochrome C Reductase complex core protein P31930, its fragments, recognition substances directed against these and / or nucle
  • the proteins mentioned belong functionally or structurally to closely related protein families.
  • the tumor markers advantageously make it possible to diagnose cancer at a very early stage and also to make statements about the future degeneration or transformation of certain tissues. Furthermore, the tumor markers are used to monitor the development of tumors.
  • the proteins mentioned also include polypeptides which are at least 80%, at least 90% and particularly at least 95%, 97% or 99% homologous to these.
  • the invention also relates to proteins modified by inversions, deletions, insertions and additions, provided that at least some of the essential functions of the wild-type proteins are present. It is also possible for natural amino acids to be replaced by synthetic amino acids in the proteins.
  • proteins mentioned therefore concern not only the naturally occurring proteins but also all modifications, mutants or derivatives, such as proteins produced by means of recombination techniques.
  • Such a protein may also include unusual amino acids and / or modifications such as alkylation, oxidation, thiol modification, denaturation and oligomerization and the like.
  • a sample in the sense of the invention is the designation for a biological good taken by sampling or a part or a small amount of such, the nature of which is to be tested chemically, biologically, clinically or similarly.
  • the sampling is carried out from the patient or from acquired humoral or cellular components of the patient in particular such that the extracted subset • an average of the entire quantity.
  • the characteristics determined by examining the sample are used to assess the amount recorded by the sample, which allows conclusions to be drawn about the total amount, for example an entire organ, such as the liver, spleen, blood or the immune system.
  • the samples can be pretreated by mixing, dividing, crushing, adding enzymes or markers or otherwise.
  • nucleic acids are nucleic acids which either encode the proteins, the recognition substances or their fragments. Of course it is possible that the nucleic acids are also hybridizing nucleic acids.
  • recognition substances are molecules which can interact with the proteins mentioned, the nucleic acids encoding them or their fragments in such a way that the proteins and / or the nucleic acids can be detected.
  • the recognition substances can in particular be specific proteins which bind the proteins mentioned, antibodies, fluorescent markers, labeled carbohydrates or lipids, antisense constructs, cDNA or mRNA molecules, their fragments or the like.
  • the recognition substances do not detect the proteins, but rather antibodies directed against them. In this case, the recognition substances would be, for example, secondary antibodies.
  • the invention also relates to a method for the detection of tumors in the biological sample of a patient, wherein in the sample a level of at least one of the proteins selected from the group consisting of type II membrane protein NP 055070 (each Swiss Prot. Number), NHP2- similar protein 1 P55769, pre-mRNA cleavage factor Im (25kD) NP008937, lysyl-tRNA synthetase Q15046, UNR-interacting protein Q9Y3F4, nuclear transport factor 2 P13662, erytrocyte phosphatase isoenzyme F P24666, prefoldin nucleate9 Q9 riboninogen unit9 C19 , transitional endoplasmic reticulum ATPase P55072, bifunctional methylenetetrahydrofolic acid dehydrogenase P13995, 47 kDa heat shock protein precursor P29043, ubiquinol-cytochrome C reductase complex core protein P31930, its fragments
  • Healthy in the sense of the invention does not have to mean the complete absence of diseases or pathogenic changes.
  • the healthy patient represents either a single patient or an average number of patients who can serve as a comparison group in such a way that a change in the level of the tumor markers mentioned can be determined.
  • a modification of the level compared to the control level means that the tumor markers mentioned have changes in their concentration or activity as protein, as nucleic acid or as antibodies compared to a control level.
  • the level is determined as a protein concentration, a protein activity, a concentration of isoforms, a DNA, an RNA concentration, a gene expression and / or a copy number of a nucleic acid which codes for one of the proteins.
  • the person skilled in the art can advantageously choose various options for determining the level of the tumor markers.
  • One possibility for example, is to determine the protein concentration using spectrographic methods.
  • the sample is brought into contact with a recognition substance of at least one of the proteins mentioned and the binding of the recognition substance to the protein is determined.
  • Recognition substances which can be used with advantage are, for example, antibodies which are directed against the protein or antisense constructs which can bind the proteins themselves or the nucleic acids which code for these proteins.
  • the antibodies, the antisense constructs or other molecules to be used as the recognition substance can be labeled or not labeled, it being possible, for example, to label them with fluorescent labels.
  • non-labeled substances Various possibilities are known to the person skilled in the art to determine the interaction of recognition substances and proteins or the nucleic acids coding for them.
  • the proteins it is also possible for the proteins to be determined on the basis of the antibodies which are directed against them.
  • a second antibody a so-called secondary antibody, would bind the antibody that originally bound the protein and thus detect it.
  • the invention also relates to a method for the treatment of tumors, the level of the proteins, the recognition substances and / or the nucleic acids being modified.
  • Various possibilities are known to the person skilled in the art for modifying the level of the substances or molecules mentioned.
  • the level of proteins can be increased or decreased. An increase is possible, for example, by adding an additional promoter to the nucleic acid encoding the corresponding protein or by increasing the activity of the original promoter. It is also possible to increase the number of copies of the nucleic acids in the corresponding target tissue, for example a tumor tissue, as a result of which more proteins are expressed.
  • the level of the proteins mentioned can also be reduced.
  • the level of type II II membrane protein NP 055070, nuclear transport factor 2 P13662, erytrocyte phosphate isoenzyme F P24666, prefoldin subunit 2 Q9UHV9 and / or bifunctional methylenetetrahydrofolic acid dehydrogenase is increased in the treatment of tumors.
  • the invention also relates to an agent for the diagnosis and / or therapy of tumor diseases, which comprises the proteins mentioned, recognition substances and the nucleic acids.
  • the invention also relates to a kit for the detection of tumor cells, the kit comprising at least one of the proteins mentioned, the nucleic acids and / or the recognition substances.
  • the invention is to be illustrated in more detail below using an exemplary embodiment, without restricting it.
  • the cell lines were treated with or without a cytostatic agent for 24 h.
  • the sensitive parental cells were treated with the dose of 20 ng / ml mitoxantrone or 250 ng / ml daunorubicin that was therapeutically achieved in the patient's serum.
  • the resistant cells were treated with the 10-fold higher concentration for the same period.
  • the cells grew in 20 cm O petri dishes and were detached in ice-cold PBS-EDTA (10 mM EDTA); adhering cells were additionally scraped off. According to Bradford [Bradford 1976], the protein was determined before lysis. After centrifugation at 500 g, the cell pellet was placed directly in 8.3 M urea,
  • Figure 7 Example of the proteome gel evaluation.
  • the gray levels of the spots were replaced by corresponding green values and overlaid with 50% transparency over the red-colored gel image to be compared. Overlapping spots that produced a gray value are under both conditions to be compared equally expressed, while shimmering green are overexpressed and shimmering red are underexpressed (labeled U in the figure).
  • Voyager STR from Applied Biosystems (20kV; Grid Voltage: 70%; Delay 200ns; positive reflector mode, low mass gate 580 Da; 5 spectra of 100 shots were collected.
  • the resulting seven 2D protein gels showed approximately the same protein spotting pattern. Approx. 2500 protein spots could be differentiated per gel.
  • the evaluation showed small differences in the cell lines ⁇ cytostatic, while the comparison between the resistant lines and the parental line showed significantly more differences. The comparisons each showed a partly balanced but mostly a ratio which was shifted in favor of overexpression: Parent cell responses to mitoxantrone
  • the parental cells after mitoxantrone treatment had 25 visibly downregulated protein spots, 9 of which were differentially expressed under other conditions (see Figure 25 and Tables 6 & 7). Except for one spot, all proteins down-regulated under various conditions were examined in the MALDITOF. Five of these proteins are in a molecular weight range between 19 and 35 kDa (proteins 1-5). The two proteins 40 and 41 were in the molecular weight range between approx. 130 and 170 kDa, each of which is the acyl-CoA binding protein, which stands for a reduced fat metabolism and speaks for a reduced cell turnover (proliferation). Protein 6 is based on the molecular weight ladder at 83 kDa.
  • the MALDITOF analysis showed that it is the beta-1 tubulin with a molecular weight of 49.8 kDa. This protein was overexpressed in the EPF85-257RDB after omitting the maintenance dose of daunorubicin.
  • MALDITOF protein determination of spots 31, 40 and 41 was not possible because the amount of protein was not sufficient.
  • spot 1 the remaining spots 2 - 5 were at an IP of pH 6.1.
  • Protein 1 corresponds to type II membrane protein (20.7kDa, pH 4.8) and is also downregulated in parental cells after daunorubicin administration, while the removal of mitoxantrone or daunorubicin leads to overexpression in the correspondingly resistant cells.
  • the protein spots 2 - 5 & 40, 41 show the same behavior.
  • the protein 38 54 kDa nuclear RNA and DNA-binding protein was also overexpressed in the mitoxantrone-resistant and daunorubicin-resistant cells and in the EPG85-257RN cells with mitoxantron, interrasante not in the parent or daunorubicin treated daunorubicin resistant cells.
  • the proteasome subunit ⁇ type 7 spot 10 was overexpressed only in the parental mitoxantrone-treated cell. Due to a lack of signal, spots 7, 9, 14, 17, 20 and 21 could not be identified.
  • the lysyl-tRNA synthetase was only used in the parental cells but in both cytostatics
  • spot 24 the proteasome ⁇ chain precursor (Spot 13) and the pre-mRNA cut factor IM (Spot 11) can be found.
  • the heterogeneous nuclear ribonucleoprotein AI (Spot 12) is overexpressed under all conditions.
  • the protein with the spot number 8 (NHP2-like protein 1) is expressed in the parental with both cytostatics and in the resistant with mitoxantrone. Parent cell responses to daunorubicin
  • the parental cells After daunorubicin treatment, the parental cells showed 30 downregulated protein spots. Of these, 7 were also differentially expressed under other conditions (see Figure 25 and Table 7). As with mitoxantrone treatment, five of the proteins which are differentially down-regulated under other conditions lie in a molecular weight range between 19 and 35 kDa (proteins 1-5; see 4.1.1.1.). The proteins 40 and 41, which were also differentially expressed under different conditions, were in the molecular weight range between approx. 130 and 170 kDa (see 4.1.1.1). All proteins had an isoelectric value in the neutral or slightly acidic pH range, only 2 protein spots that were specifically down-regulated under these conditions were in the slightly basic range.
  • spots 3 and 4 are each the acyl-CoA binding protein.
  • One of the two spots that are specifically differentially expressed by means of MALDITOF is the ubiquitin conjugation enzyme E2-17 (spot 16). The other spot could not be because of keratin contamination. Keratin cannot be determined. overexpression
  • spot 18 corresponds to the RHO GDP dissociation inhibitor that was found to be overexpressed in a mitoxantrone-resistant fibrosarcoma cell line, while the others could not be determined for various reasons (Table 7).
  • Spot 26 did not produce a database result, with ATP synthetase being a candidate.
  • the glutathione S-transferase is up-regulated in the two resistant lines compared to the parental lines, and the expression in the mitoxantrone-resistant lines can be increased by adding mitoxantrone. For technical reasons, spots 17, 32 and 37 did not give an evaluable signal.
  • beta-1 chain of tubulin spot 7
  • heterogeneous nuclear ribonucleoprotein AI spots 12 & 23
  • the beta-1 chain of tubulin is also differentially expressed in the two parental cells with mitoxantrone and daunorubicing.
  • the resistant cells showed recognizable down-regulated protein spots compared to the parental cells 62. Of these, 29 became differential under other conditions are therefore not specific for this resistance
  • the proteins found are in the molecular weight range of approximately 19-150 kDA and an IP of approximately 3.5-9.
  • the proteins differentially expressed under other conditions are also at
  • spots 3 and 4 which each correspond to the acyl-CoA binding protein, type II membrane-binding protein (spot 1), epidermal fatty acid-binding protein (spot 28) and iso-enzyme F of erythrocyte acid phosphatase 1 (spot 29) , while spots 5, 40 and 41 each gave no evaluable signal.
  • Spots 27 and 30 and 31 were expressed specifically under these conditions. These are the nuclear transport factor 2 (27) and the prefoldin subunit 2, while the spot 31 gave no result. overexpression
  • spots were examined, one of which expresses differentially in this comparison (spot 39). These are heterogeneous nuclear ribonucleoprotein A2 / B1.
  • the proteins differentially expressed under other conditions are: the NHP2-like protein 1 (spot 8), the heterogeneous nuclear ribonucleoprotein AI (spots 12 & 23), the UNR-interacting protein (spot 25) the heterogeneous nuclear ribonucleoprotein C1 / C2 ( Spots 33, 34), the transitional endoplasmic reticulum ATPase (spot 35), the protein 54 kDa nuclear RNA and DNA binding protein (spot 38) and the glutathione S-transferase (spot 48).
  • Spot 37 gave no signal.
  • the heterogeneous nuclear ribonucleoprotein A2 / B1 and the spot 36 which gave no signal, were expressed.
  • the resistant cells had visibly downregulated protein spots compared to the parental cells 61. Of these, 13 were also differentially expressed under other conditions, so they are not specific for this resistance (see Figure 30 and Table 7).
  • the proteins found are in the molecular weight range of approx. 19 - 150 kDA and an IP of approx. 3 - 10.
  • the proteins differentially expressed under other conditions are largely clustered in the acid / neutral low molecular weight range (pH 19 - 35; Figure 30, left) Blot bottom left).
  • the 11 proteins that were downregulated in the resistant cells are among the proteins that are differentially expressed under other conditions.
  • spots 3 and 4 include the both spots 3 and 4, each corresponding to the acyl-CoA binding protein, the beta-1 chain of tubulin (spot 6), the ubiquitin conjugation enzyme E2-17kDa (spot 16), the epidermal fatty acid binding protein (spot 28) and the isozyme F of the erythrocyte acid phosphatase 1 (spot 29), while the spots 2, 5, 15, 31, 40 and 41 each gave no evaluable signal.
  • the isozyme F of erythrocyte acid phosphatase 1 only occurs in both resistant cells compared to the parental cells (EPG85-257RN and RDB).
  • spots 45 - 47 & 49 - 51 14 spots were examined, six of which were specific overexpressed in this comparison (spots 45 - 47 & 49 - 51).
  • Spot 45 behind which there are only 3 different proteins: the mitochondral precursor of the aspartate aminotransferase, the precursor of the collagen-binding protein 2 and the precursor of the 47kDa heat shock protein.
  • This also includes Annexin I (Spot 46), the Eta type of protein kinase C (Spot 47), the Cor protein of Ubiquinol cytochrome C reductase (Spot 49) and the 54kDa nuclear RNA and DNA binding protein (Spots 50 & 51).
  • the proteins differentially expressed under other conditions are: the heterogeneous nuclear ribonucleoprotein AI (spots 12 & 23), the UNR interacting protein (spot 25), the heterogeneous nuclear ribonucleoprotein C1 / C2 (spots 33, 34) and the protein 54 kDa nuclear RNA and DNA binding protein (spot 38) and the glutathione S-transferase (spot 48). Spots 7 & 32 gave no signal.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Electrochemistry (AREA)
  • Organic Chemistry (AREA)
  • Biophysics (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Chemical & Material Sciences (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention l'utilisation de la protéine membranaire de type II NP 055070 (respectivement numéro prot. suisse), protéine 1 P55769 semblable à NHP2, facteur de clivage pré-ARNm dans (25kD) NP008937, synthétase Lysyl-ARNt Q15046, protéine Q9Y3F4 d'interaction avec UNR, facteur de transport nucléaire 2 P13662, isoenzyme F de phosphatase d'érythrocytes F P24666, sous-unité Prefoldin 2 Q9UHV9, ribonucléoprotéine nucléaire C1/C2 P07910 hétérogène, réticulum-ATPase P55072 endoplasmique transitionnelle, déshydrogénase d'acide méthylènetétrahydrofolique bifonctionnelle P13995, 47 kDa précurseur de protéine choc thermique P29043, protéine de noyau complexe de réductase ubichinol-cytochrome Cn P31930, leurs fragments, les substances de détection dirigées vers ces derniers et/ou les acides nucléiques codant pour ces derniers, pour la production d'un produit de diagnostic, de traitement prophylactique ou thérapeutique de tumeurs.
PCT/EP2003/006748 2002-06-26 2003-06-26 Marqueurs tumoraux et leur utilisation aux fins de diagnostic et traitement de maladies tumorales Ceased WO2004003564A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003246592A AU2003246592A1 (en) 2002-06-26 2003-06-26 Tumour marker and the use thereof for the diagnosis and treatment of tumour diseases

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10229386.4 2002-06-26
DE10229386 2002-06-26

Publications (2)

Publication Number Publication Date
WO2004003564A2 true WO2004003564A2 (fr) 2004-01-08
WO2004003564A3 WO2004003564A3 (fr) 2004-12-29

Family

ID=29796039

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2003/006748 Ceased WO2004003564A2 (fr) 2002-06-26 2003-06-26 Marqueurs tumoraux et leur utilisation aux fins de diagnostic et traitement de maladies tumorales

Country Status (2)

Country Link
AU (1) AU2003246592A1 (fr)
WO (1) WO2004003564A2 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102124104A (zh) * 2008-08-18 2011-07-13 财团法人首尔大学校产学协力财团 通过调节赖氨酰tRNA合成酶的细胞水平控制癌症转移或癌细胞移动的方法
US8562976B2 (en) 2004-01-22 2013-10-22 University Of Miami Co-enzyme Q10 formulations and methods of use
US9896731B2 (en) 2009-05-11 2018-02-20 Berg Llc Methods for treatment of oncological disorders using an epimetabolic shifter (coenzyme Q10)
US9901542B2 (en) 2013-09-04 2018-02-27 Berg Llc Methods of treatment of cancer by continuous infusion of coenzyme Q10
US10376477B2 (en) 2011-04-04 2019-08-13 Berg Llc Method of treating or preventing tumors of the central nervous system
US10588859B2 (en) 2007-03-22 2020-03-17 Berg Llc Topical formulations having enhanced bioavailability
US10668028B2 (en) 2008-04-11 2020-06-02 Berg Llc Methods and use of inducing apoptosis in cancer cells
US10933032B2 (en) 2013-04-08 2021-03-02 Berg Llc Methods for the treatment of cancer using coenzyme Q10 combination therapies
US10973763B2 (en) 2011-06-17 2021-04-13 Berg Llc Inhalable pharmaceutical compositions
US11400058B2 (en) 2010-03-12 2022-08-02 Berg Llc Intravenous formulations of coenzyme Q10 (CoQ10) and methods of use thereof
US12303471B2 (en) 2015-11-16 2025-05-20 Bpgbio, Inc. Methods of treatment of temozolomide-resistant glioma using coenzyme Q10

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1358349A2 (fr) * 2000-06-05 2003-11-05 Avalon Pharmaceuticals Determination de gene du cancer et recherche therapeutique utilisant des ensembles de genes signature

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8562976B2 (en) 2004-01-22 2013-10-22 University Of Miami Co-enzyme Q10 formulations and methods of use
US8586030B2 (en) 2004-01-22 2013-11-19 University Of Miami Co-enzyme Q10 formulations and methods of use
US8771680B2 (en) 2004-01-22 2014-07-08 University Of Miami Topical co-enzyme Q10 formulations and methods of use
US10588859B2 (en) 2007-03-22 2020-03-17 Berg Llc Topical formulations having enhanced bioavailability
US10668028B2 (en) 2008-04-11 2020-06-02 Berg Llc Methods and use of inducing apoptosis in cancer cells
CN102124104A (zh) * 2008-08-18 2011-07-13 财团法人首尔大学校产学协力财团 通过调节赖氨酰tRNA合成酶的细胞水平控制癌症转移或癌细胞移动的方法
US10519504B2 (en) 2009-05-11 2019-12-31 Berg Llc Methods for treatment of oncological disorders using epimetabolic shifters, multidimensional intracellular molecules, or environmental influencers
US10351915B2 (en) 2009-05-11 2019-07-16 Berg Llc Methods for treatment of oncological disorders using an epimetabolic shifter (Coenzyme Q10)
US9896731B2 (en) 2009-05-11 2018-02-20 Berg Llc Methods for treatment of oncological disorders using an epimetabolic shifter (coenzyme Q10)
US11028446B2 (en) 2009-05-11 2021-06-08 Berg Llc Methods for treatment of oncological disorders using an epimetabolic shifter (coenzyme Q10)
US12209285B2 (en) 2009-05-11 2025-01-28 Bpgbio, Inc. Methods for treatment of oncological disorders using an epimetabolic shifter (coenzyme Q10)
US11400058B2 (en) 2010-03-12 2022-08-02 Berg Llc Intravenous formulations of coenzyme Q10 (CoQ10) and methods of use thereof
US10376477B2 (en) 2011-04-04 2019-08-13 Berg Llc Method of treating or preventing tumors of the central nervous system
US11452699B2 (en) 2011-04-04 2022-09-27 Berg Llc Method of treating or preventing tumors of the central nervous system
US10973763B2 (en) 2011-06-17 2021-04-13 Berg Llc Inhalable pharmaceutical compositions
US10933032B2 (en) 2013-04-08 2021-03-02 Berg Llc Methods for the treatment of cancer using coenzyme Q10 combination therapies
US9901542B2 (en) 2013-09-04 2018-02-27 Berg Llc Methods of treatment of cancer by continuous infusion of coenzyme Q10
US11298313B2 (en) 2013-09-04 2022-04-12 Berg Llc Methods of treatment of cancer by continuous infusion of coenzyme Q10
US12303471B2 (en) 2015-11-16 2025-05-20 Bpgbio, Inc. Methods of treatment of temozolomide-resistant glioma using coenzyme Q10

Also Published As

Publication number Publication date
AU2003246592A1 (en) 2004-01-19
WO2004003564A3 (fr) 2004-12-29

Similar Documents

Publication Publication Date Title
DE69333670T2 (de) Vom mage-3-gen abgeleitetes und von hla-a1 präsentiertes, isoliertes nonapeptid und dessen anwendungen
DE69334186T2 (de) Vom MAGE-3-Gen en abgeleitetes und von HLA-A1 präsentiertes, isoliertes Nonapeptid und dessen Anwendungen
DE69433518T4 (de) Nukleinsäure, die für einen tumor abstossungsantigenvorläufer kodiert
DE3750738T2 (de) Menschliche DNS für die Diagnose von Glioma-retinae.
DE3650416T2 (de) Zelluläres verfahren zur bestimmung des originalen gewebes.
DE68928491T2 (de) Erzeugnisse und verfahren zur regelung der suppression von neoplastischen phenotypen
EP1318407B1 (fr) Utilisation de l'aldose-1-epimerase (mutarotase) pour le diagnostic des infections et de la septicémie
EP1356106A2 (fr) Procede pour la determination in vitro des agressions ou du vieillissement cutanes
DE69633272T2 (de) Methoden zur Krebsbehandlung und -kontrolle
DE60219809T2 (de) Verbindungen und Verfahren zur Nachweiss von Karzinomen und deren Vorstufen
EP2052254A2 (fr) Biomarqueur d'hépatite
DE69329656T2 (de) Methoden zur detektion und behandlung von individuen mit abnormalen hla-a2/tyrosinase-peptidantigenen exprimierenden zellen
DE3879085T2 (de) Snrnp-a-antigen und fragmente davon.
EP2978402B1 (fr) Polyribonucléotide stabilisé codant pour une protéine fibreuse élastique
EP4435106A1 (fr) Nouvel aptamère, et composition pour l'amélioration des fonctions cognitives et la lutte contre le vieillissement comprenant un aptamère comme principe actif
EP1318406A1 (fr) Utilisation de la Glycine-N-Acyl-Transférase (GNAT) pour le diagnostic et la thérapie des maladies inflammatoires et de la septicémie
DE4002981C2 (de) Humane, Epididymis-spezifische Polypeptide und deren Verwendung zur Therapie und Diagnose männlicher Infertilität
WO2007012449A1 (fr) Frizzled 9 en tant que marqueur tumoral
DE69530410T2 (de) Methoden zur identifizierung von individuen, die an einer zellulären abnormalität leiden
EP3149485B1 (fr) Procédé de diagnostic d'une maladie médiée par la voie alterne du système du complément ou d'un risque pour celle-ci
EP1007671B1 (fr) Gene ii de fanconi
DE69830169T2 (de) Nachweis und behandlung von krebs
DE10351627B4 (de) Modulation der Angiogenese durch Bartonella henselae
EP2601308B1 (fr) Variant d'epissage de aspp2
WO2000024886A1 (fr) Le gene prv-1 et son utilisation

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP