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WO2004063394A2 - Utilisation de substances se fixant a fabp4 pour le diagnostic et le traitement du carcenome de la vessie - Google Patents

Utilisation de substances se fixant a fabp4 pour le diagnostic et le traitement du carcenome de la vessie Download PDF

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Publication number
WO2004063394A2
WO2004063394A2 PCT/DE2004/000029 DE2004000029W WO2004063394A2 WO 2004063394 A2 WO2004063394 A2 WO 2004063394A2 DE 2004000029 W DE2004000029 W DE 2004000029W WO 2004063394 A2 WO2004063394 A2 WO 2004063394A2
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Prior art keywords
fabp4
substance
protein
tumor
peptide
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German (de)
English (en)
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WO2004063394A3 (fr
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Bernd Hinzmann
Edgar Dahl
Thomas Specht
Christian Pilarsky
Alexander Herr
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/112—Disease subtyping, staging or classification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/136—Screening for pharmacological compounds
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value

Definitions

  • the invention relates to new uses of FABP4 or sequences derived therefrom for screening for substances which bind to it, and to the use of substances which bind to FABP4 for the diagnosis and / or treatment of bladder carcinoma.
  • FABP4 stands for Fatty Acid Binding Protein 4.
  • FABP4 belongs to a family of homologous, cytosolic localized proteins.
  • FABP4 is also called adipocyte fatty acid binding protein (A-FABP), aP2 (in the mouse) or adipocyte lipid binding protein (ALBP).
  • A-FABP adipocyte fatty acid binding protein
  • ABP2 in the mouse
  • ABP adipocyte lipid binding protein
  • FABPs are characterized by largely tissue-specific expression.
  • FABP4 is expressed in normal tissue in adipocytes and accounts for approximately 1% of the total amount of cytosolic protein. By binding the. Fatty acids on FABPs can be transported and stored in the cell's aqueous environment.
  • FABP4 The expression of FABP4 in urothelial cells in normal and tumor tissues is very different.
  • a functional relationship between FABP expression and tumor development has not yet been elucidated. Overall, a very heterogeneous picture emerges for the expression ester, which is why it cannot be predicted whether or in which tumors overexpression will take place and what such overexpression ultimately means.
  • Bladder cancer is the second most common urological tumor. It occurs in men with a frequency of 245 to 100,000 and in women from 65 to 100,000. Among cancer deaths, bladder cancer ranks fourth in men and sixth in women. Treatment is usually through cystectomy, i.e. by partially or completely removing the bladder. This often leads to further complications for the sick person.
  • Bladder cancer develops through the degeneration of individual urothelial cells.
  • the urothelium is the layer of cells that shields the inside of the body from the urine that is formed. It lines the lumen of the renal pelvis, ureter, bladder and urethra.
  • Bladder cancer develops almost completely (> 93%) as adenocarcinoma and is characterized by the strong tendency to recurrence, the regular recurrence even after treatment.
  • the development of bladder cancer is mainly due to the influence of chemical noxae, such as aromatic amines, but mainly to smoking as a cause recycled. It can be diagnosed relatively early and take two forms.
  • the invasive forms grow into the tissue and, if left untreated, lead to the most severe symptoms, such as Ly. ⁇ ph node involvement and metastases. The deaths arise almost exclusively from this second group. It is characteristic of the course that the papillary tumors very often remain stable and therefore show no progress towards the dangerous invasive forms. In 10-20% of cases, however, there is a progression to the aggressive, muscle-invasive tumors within 5 years.
  • a number of genes have so far been examined for their suitability as a prognostic marker in bladder cancer. It is of primary interest whether a patient with non-invasive, papillary tumors remains stable at this stage or whether he will develop invasive forms.
  • the markers examined so far mainly include p53, p21 and the retinoblastoma gene Rb. However, none of the markers mentioned allows a prognosis for an individual patient with sufficient certainty (Marberger et al., Eur. Urol., 40/5, Curric Urol 1-9 (2001)). More recent, commercially available tests (BTA-STAT, NMP22) focus more on the detection of urothelioma than on the prognosis of the course.
  • the invention is therefore based on the technical problem of specifying pharmaceutical compositions for diagnosis, in particular for prognosis for progression or progression, and / or for treating bladder carcinoma and means for identifying them.
  • a nucleic acid coding for FABP4 and / or a FABP4 peptide or protein for the detection of bladder carcinoma or for the detection of a risk of the disease from such a carcinoma or for the detection of a risk of a progression of a papillary urinary carcinoma to one teaches invasive carcinoma, a urothelial cell tissue sample, in particular a urinary bladder urothelial cell tissue sample, being examined for transcription or over-transcription of FABP4 RNA or for expression or over-expression of a FABP4 protein.
  • a nucleic acid coding for FABP4 or a detector substance that binds to FABP4 protein or peptide, preferably containing a reporter group, can be used, whereby binding of said nucleic acid and / or said protein or peptide to the detector substance is detected semi-quantitatively or quantitatively.
  • the invention further teaches a Testsyste to the (in vitro) detection of an aforementioned cancer or risk of disease thereto or Progression- sprognose comprising, means for quantitative measurement of the expression of FABP4 in tissue samples, said means for example, means for Amplification and specific Detection of FABP4 RNA and / or a detector substance, in particular specific for FABP4 protein, can be.
  • the invention further teaches the use of a FABP4 RNA or a FABP4 protein or peptide for screening for substances which bind to it, in particular prospective active substances for modulating, in particular inhibiting, said RNA or said protein or peptide, or prospective detector substances, a prospective substance or a Mixture of such prospective substances is contacted with said RNA or said protein or peptide, binding events being determined using a binding assay, and a binding prospective substance being selected, if appropriate after deconvolution.
  • the invention further teaches a screening system for determining active substances suitable for the treatment of the above tumor diseases, comprising a FABP4 nucleic acid or a FABP4 protein or peptide, means for determining (in vitro) binding events to the FABP4 nucleic acid or to the FABP4 protein or peptide, and / or means for determining the (in vitro) activity of FABP4 protein.
  • FABP4 can be present in a cell-free or a cell-based system, the latter in particular having urothelial cells of the urogenital tract, in particular the urinary bladder, or a cell line developed therefrom.
  • Means for determining binding events can, for example, naturally include substances or association partners that bind naturally in normal cells or in tumor cells, for example to FABP4 protein, with their (free) concentration or concentration change when prospective active substances and / or detector substances are added, a competitive binding of a binding active substance or Detector substance is determined.
  • Such means can also include physical or physico-chemical methods, such as X-ray structure analysis and / or NMR, in particular two-dimensional 1H / 1H or 15N / 1H or 14C / 1H correlation spectroscopy.
  • spectra are compared with each other before and after the addition of a prospective active substance or detector substance, and in the event of changes, a binding event is determined.
  • Spectra or the like of either FABP4 or the prospective substance or a combination of both can be used.
  • all other standard methods of determining binding events and / or protein activities can also be used.
  • a prospective substance or several substances, spatially separated from one another
  • a binding event is then determined after application and subsequent rinsing by detection, possibly locally resolved, of the label-bound FABP4s.
  • FABP4 can be immobilized and a labeled prospective substance or a mixture thereof is applied. Binding events are determined analogously to the variant above.
  • the invention teaches the use of a substance that inhibits or binds to FABP4 for the production of a pharmaceutical composition for the treatment and / or diagnosis of bladder carcinoma or prognosis of progression in bladder carcinoma diseases.
  • the substance can be an antibody which can be obtained by immunizing a non-human mammal with an FABP4 peptide or protein with cDNA coding therefor transfected cells, with tumor cells expressing such a peptide or protein endogenously, or with recombinantly produced FABP4 peptides or proteins, or a phage display antibody.
  • the substance can also be a mimicry compound of an antibody against an FABP4 peptide or protein.
  • the substance can be an apta er, an antisense RNA, a ribozyme or an siRNA against FABP4 nucleic acids.
  • the substance can additionally carry a cytotoxic and / or immune-stimulating component.
  • the above substances binding to FABP4 protein specifically bind to the FABP4 protein when used for therapeutic purposes and modulate its biological activity. This is not necessary in the case of fusion or connection of the substance with a cytotoxic component. This is not necessary to continue when the substance of the extraction is used an anti-idiotypic antibody which 'will be recognized as foreign by the immune system of a patient due to its non-humanized form, and otherwise a FABP4 antigen presented to the immune system.
  • the pharmaceutical composition can be prepared for any application, for example iv or ip injection.
  • a fitting-out to the local Applika ⁇ tion in tumor cells containing tissue is recommended in the case of using a cytotoxic component.
  • the invention can be used in the context of a method for the diagnosis or prognosis of progression of a tumor disease of the bladder carcinoma, whereby one Detector substance is applied in one embodiment with a reporter group in the tissue to be examined, if appropriate in vitro after tissue removal, the tissue to be examined then being subjected to a detection method stage which is sensitive to the reporter group, and in the case of the detection of a defined one Minimum values of the reporter group in the tissue, the tissue is qualified as containing tumor cells or is classified as being at risk of progression or not at risk of progression, and a method for treating a bladder tumor disease, a pharmaceutical composition according to the invention being administered to a patient in a physiologically effective dose.
  • a tissue sample can additionally or alternatively be examined for FABP4 expression using a test system according to the invention.
  • the invention is based in particular on the finding that FABP4 is expressed differently in different papillary tumors of bladder carcinoma, ie in said tumor tissues the expression is higher in the case of such papillary carcinomas which later become invasive, compared to normal cells of the same tissue, and in the case of papillary carcinomas which remain stable, on the other hand, low, and the technical teaching which can be derived therefrom that FABP4 can be used as a target molecule in diagnosis, in particular prognosis of progression, and therapy or prophylaxis, in particular of invasive tumor diseases.
  • FABP4 can therefore serve as a specific marker for identifying tumor cells in said tumor tissues which have a risk of forming invasive tumor tissues.
  • the inhibition of FABP4 offers the opportunity to intervene in the tumor-specific FABP4 associations with other processes in the tumor cells and thus ultimately to disrupt the tumor cell-specific metabolism and to die or at least inhibit the growth of the tumor cells, but in particular inhibit the growth To contribute to progression to invasive tumors.
  • a sample from a tissue which is identified as tumor tissue by other methods in advance of a treatment with a pharmaceutical composition according to the invention and to examine the tissue sample for expression or overexpression of FABP4.
  • a detector substance according to the invention can be used to test in vivo for FABP4 dependency. If expression or overexpression of FABP4 compared to normal tissue of the same type is found, the use of the pharmaceutical composition according to the invention is indicated.
  • the substance binding to FABP4 additionally carries a cytotoxic and / or immunostimulating component. This then ultimately leads to the fact that almost exclusively tumor cells are killed, either by cytotoxicity or by attack by the stimulated immune system, while normal cells are practically completely preserved in the tissue.
  • the binding substance itself does not have to have an inhibitory effect on FABP4, since the binding substance then only has to function as a marker which carries the components to target tumor cells. If a cytotoxic component is used, it will be particularly recommended if the pharmaceutical composition is prepared for local application in tissue containing tumor cells, for example for injection.
  • FIGS. 1 and 2 The nucleic acid and protein sequence are shown in FIGS. 1 and 2 (SEQ ID NO. 1 and 2).
  • FABP4 is used for all human isoforms, known or new, based on nucleic acids or amino acids. These terms also include the short sequences disclosed in the context of this description, which originate from the isoforms, for example immunization sequences. Also included are homologs, the homology being at least 80%, preferably more than 90%, most preferably more than 95%, calculated with the program MEGALIGN (DNASTAR LASERGENE) in the version current at the time of the present application. In the case of the nucleic acid sequences, complementary or allelic variants are also included.
  • sequences comprises only partial sequences of the explicitly disclosed sequences, for example one or more exons, or sequences complementary thereto, with the proviso that, in the case of the nucleic acids, these partial sequences have a length sufficient for hybridization with a nucleic acid according to the invention, at least 50 bases , and, in the case of the proteins or peptides, bind to a protein- or peptide-specific target molecule with at least the same affinity.
  • all nucleic acids hybridizing with nucleic acids according to the invention are included, namely those which are under stringent conditions (5 ° C. to 25 ° C.
  • the invention also includes expression cassettes, ie one or more of the nucleic acid sequences according to the invention with at least one operatively linked control or regulatory sequence.
  • Such an expression cassette can also comprise a sequence for a known protein, a fusion protein being formed in the course of the translation from a known protein and a protein or peptide according to the invention.
  • Antisense sequences to the above nucleic acid sequences are also included.
  • RNA and correlating DNA and vice versa are included, as are genomic DNA and correlated cDNA and vice versa.
  • These partial sequences can be incorporated into nucleic acid or protein or peptide sequences that are otherwise different from FABP4.
  • treatment also includes prophylaxis, especially prophylaxis of progression to invasive tumors.
  • An inhibitor is a compound or substance which either inhibits the formation of FABP4 protein or reduces the activity of FABP4 protein formed, based on the FABP4 activity in the absence of the inhibitor.
  • an inhibitor can be a substance that interferes with the cascade of FABP4.
  • an inhibitor can be a substance which binds with the FABP4 formed, in such a way that further physiological interactions with endogenous substances are at least reduced.
  • Mimicry molecules are compounds that simulate the variable region, in particular the binding region of an antibody, and bind to a target molecule in the same place as the underlying antibody.
  • antibody includes polyclonal antibodies, monoclonal antibodies, non-human, humane and humanis ⁇ ated antibodies and phage display antibodies but also chimeric antibodies as well as specific fragments of the light and / or heavy chain of the variable region underlying antibodies of the above type and anti-idiotypic antibodies. The production or extraction of such antibodies with predetermined immunogens is well known to the average tachometer and need not be explained in more detail.
  • the term antibody also includes bispecific antibodies. Bispecific antibodies combine a defined immune cell activity with a specific tumor cell recognition, whereby tumor cells are killed. A bispecific antibody binds on the one hand to a trigger molecule of the immune effector cell (eg CD3, CD16, CD64) and on the other hand to antigens of the tumor target cell.
  • a trigger molecule of the immune effector cell eg CD3, CD16, CD64
  • Suitable counterions for ionic compounds are, for example, Na ", K Li or cyclohexylammonium.
  • Suitable solid or liquid pharmaceutical preparation forms are, for example, granules, powders, dragees, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, Drops or injectable solutions (iV, ip, im) as well as preparations with a protracted active ingredient release, in the production of which conventional auxiliaries such as carriers, explosives, binders, coating agents, swelling agents, lubricants or lubricants, flavors, sweeteners and solubilizers, Magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talcum, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil
  • a pharmaceutical composition according to the invention can be produced by mixing at least one inhibitor used according to the invention in a defined dose with a pharmaceutically suitable and physiologically compatible carrier and, if appropriate, other suitable active ingredients, additives or auxiliaries with a defined inhibitor dose and preparing the desired dosage form.
  • Tumor cells express FABP4 differentially when normal cells of the same tissue type (of the same or different volunteers) do not express it. Tumor cells overexpress FABP4 specifically or differentially if FABP4 is expressed at least twice as much as normal cells of the same tissue type.
  • Cytotoxic components or groups are compounds which directly or indirectly induce apoptosis or lead to necrosis or at least inhibit growth.
  • radioisotopes for example 188Re, 213Bi, 99mTc, 90Y, 131J, 177Lu
  • such groups or compounds can in particular be cytostatics which are used in tumor therapy.
  • alkylating agents for example mechlorethamine, ifosfamide, chlorambucil, cyclophosphide, melphalan, alkylsulfonates, busulphan, nitrosoureas, carmustine, lomustine, semustin, triazenes, dacarbazine
  • antimetabolites for example folic acid antagonists, pyrididine
  • Analogs fluorouracil, fluorordesoxyuridine, cytarabine, gemcitabine, purine analogs, mercapturin
  • mitosis inhibitors e.g.
  • the coupling takes place in such a way that the affinity for FABP4 is reduced by no more than 90%, preferably 50%, based on the substance without a cytostatic group, and the cytostatic effect of the group is not reduced by more than 90%, preferably 50%, based on the compound without substance.
  • An immunostimulating component is usually a protein or an effective component thereof, which stimulates cells of the immune system.
  • cytokines such as M-CSF, GM-CSF, G-CSF, interferons, such as IFN-alpha, -beta, -gamma, interleukins such as IL-1 to -16 (except -8), human LIF, chemokines such as Rantes, MCAF, MIP-1-alpha, -beta, NAP-1 and IL-8.
  • a reporter group is an atom, molecule or a compound which, in conjunction with an assay based thereon, enables the detection of the reporter group and the compound or substance thus connected to the reporter group.
  • reporter groups and associated detection methods are: 32P labeling and intensity measurement using phosphoimager. Many other examples are known to the person skilled in the art and do not need to be listed in detail.
  • a substance that binds to FABP4 can be a substance that binds to a FABP4 protein or a FABP4 RNA.
  • Definitions expanded in the context of the above definition in relation to the narrow sense of the word also include the specific terms in the narrow sense of the word.
  • FIG. 1 FABP4 nucleic acid sequence
  • Example 1 The samples from Example 1 were subjected to an expression analysis on FABP4 using the GeneChip technology (Affimetrix). The results are shown in FIG. 3. The median expression values of different stages and subtypes of bladder cancer are shown. The values for the pTA tumors with and without subsequent progression are highlighted in dark. It can be seen that the median of the progressive tumors is 16x higher than that of the non-progressive tumors, i.e. Expression of the FABP4 gene is found almost exclusively in the tumor epithelium of patients in whom the tumor later took an invasive course. Specifically, FABP4 was strongly overexpressed in 17 of 21 tissues that showed progression to invasive tumors. In contrast, increased expression was only found in 3 of 24 tissues that showed a stable course.

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Abstract

L'invention concerne l'utilisation de FABP4 pour le diagnostic et le traitement de tumeurs urogénitales, en particulier du carcinome de la vessie, ainsi que pour le criblage de substances devant être utilisées à ces fins.
PCT/DE2004/000029 2003-01-10 2004-01-08 Utilisation de substances se fixant a fabp4 pour le diagnostic et le traitement du carcenome de la vessie Ceased WO2004063394A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE2003100861 DE10300861A1 (de) 2003-01-10 2003-01-10 Verwendung von an FABP4 bindenden Substanzen zur Diagnose und Behandlung des Harnblasenkarzinoms
DE10300861.6 2003-01-10

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WO2004063394A3 WO2004063394A3 (fr) 2004-10-14

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009027527A3 (fr) * 2007-08-30 2009-07-02 Santaris Pharma As Composes antagonistes d'arn permettant la modulation de fabp4/ap2
CN110438127A (zh) * 2019-08-09 2019-11-12 中国药科大学 抑制FABP4靶基因表达的siRNA及其应用

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9499864B2 (en) 2003-11-03 2016-11-22 Aab Patent Holding Aps Expression of FABP4 and other genes associated with bladder cancer progression

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BENNETT J H ET AL.: "Immunohistochemical identification of tumours of adipocytic differentiation using an antibody to aP2 protein" JOURNAL OF CLINICAL PATHOLOGY, Bd. 48, 1995, Seiten 950-954, XP008031677 *
CELIS A ET AL.: "Short-term culturing of low-grade superficial bladder transitional cell carcinomas leads to changes in the expression levels of several proteins involved in key cellular activities" ELECTROPHORESIS, Bd. 20, Nr. 2, 1999, Seiten 355-361, XP002287087 *
CELIS J E ET AL.: "Loss of adipocyte-type fatty acid binding protein and other protein biomarkers is associated with progression of human bladder transitional cell carcinomas" CANCER RESEARCH, Bd. 56, Nr. 20, 1999, Seiten 4782-4790, XP001189628 *
GROMOVA I ET AL.: "Protein abundancy and mRNA levels of the adipocyte-type fatty acid binding protein correlate in non-invasive and invasive bladder transitional cell carcinomas" INTERNATIONAL JOURNAL OF ONCOLOGY, Bd. 13, 1998, Seiten 379-383, XP008031678 *
VAN DONGEN M J P ET AL.: "Structure-based screening as apllied to human FABP4: A highly efficient alternative to HTS for hit generation" THE JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Bd. 124, 9. Oktober 2002 (2002-10-09), Seiten 11874-11880, XP002287088 *
YANG T T ET AL.: "aP2 protein expression as a diagnostic marker in soft tissue tumours" SARCOMA, Nr. 5, 2001, Seiten 139-142, XP008031680 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009027527A3 (fr) * 2007-08-30 2009-07-02 Santaris Pharma As Composes antagonistes d'arn permettant la modulation de fabp4/ap2
CN110438127A (zh) * 2019-08-09 2019-11-12 中国药科大学 抑制FABP4靶基因表达的siRNA及其应用

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DE10300861A1 (de) 2004-07-22

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