EP1292706A2 - Verfahren zum nachweis von ginko biloba in pflanzenextrakten durch bestimmung des genprofils - Google Patents

Verfahren zum nachweis von ginko biloba in pflanzenextrakten durch bestimmung des genprofils

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Publication number
EP1292706A2
EP1292706A2 EP01920817A EP01920817A EP1292706A2 EP 1292706 A2 EP1292706 A2 EP 1292706A2 EP 01920817 A EP01920817 A EP 01920817A EP 01920817 A EP01920817 A EP 01920817A EP 1292706 A2 EP1292706 A2 EP 1292706A2
Authority
EP
European Patent Office
Prior art keywords
cdna
treated
untreated
cells
gene regulation
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.)
Withdrawn
Application number
EP01920817A
Other languages
English (en)
French (fr)
Inventor
Katy Drieu
Vassilios Papadopoulos
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.)
Ipsen Pharma SAS
Georgetown University
Original Assignee
Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS
Georgetown University
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 Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS, Georgetown University filed Critical Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS
Publication of EP1292706A2 publication Critical patent/EP1292706A2/de
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • 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
    • C12Q1/6813—Hybridisation assays
    • C12Q1/6834—Enzymatic or biochemical coupling of nucleic acids to a solid phase
    • C12Q1/6837—Enzymatic or biochemical coupling of nucleic acids to a solid phase using probe arrays or probe chips
    • 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
    • C12Q1/6809—Methods for determination or identification of nucleic acids involving differential detection

Definitions

  • the present invention is directed to a method of establishing an "identity" of Ginkgo biloba leaves or isolated ginkgolide B (GKB), a component of the extract of Ginkgo biloba leaves, by obtaining a "gene regulation profile".
  • the invention is also directed to a method of verifying the identity of a Ginkgo biloba extract by comparing the gene regulation profile of a Gingko biloba extract of unknown or questionable origin with the gene regulation profile of a Gingko biloba extract of known origin.
  • known origin refers to the commercial source of the extract.
  • a preferred aspect of the present invention is where the Ginkgo biloba extract of known origin is EGB 761®, produced and marketed by IPSEN of Paris, France.
  • this invention is directed to a method for determining the authenticity of an extract of unknown origin purporting to be EGB 761®.
  • the present invention is further directed to a method of establishing a gene expression profile of Ginkgolide A, Ginkgolide B or any other component isolated from a Ginkgo biloba extract, more particularly, from EGB 761®.
  • composition is based on control over the composition and the consistency of the biological activity profile of a manufactured batch. This standardization and control provides reproducible material in the predictable and consistent treatment of patients. Such use of standardization and control to guard against the marketing of counterfeit extracts purporting to be EGB 761® is beneficial to patients since it assures patients that they are obtaining/receiving an extract with a particular biological activity profile.
  • Ginkgo biloba is one of the most ancient trees, and extracts from its leaves have been used in traditional medicine for several hundred years. There are numerous studies describing the beneficial effects of Ginkgo biloba extracts on patients with disturbances in vigilance, memory, and cognitive functions associated with aging and senility, and on those with all types of dementias, mood changes, and the ability to cope with daily stressors.
  • a standardized extract of Ginkgo biloba leaves, termed EGB 761® has been used in most of these studies. This extract is also known to have cardioprotective effects (DeFeudis F.V. Ginkgo biloba extract (EGB 761®): from chemistry to clinic. Ullstein Medical, Wisbaden, Germany. 400 pp.
  • EGB 761® Ginkgo biloba Extract
  • the extract contains 24% ginkgo-flavone glycosides, 6% terpene lactones (ginkgolides and bilobalide), about 7% proanthocyanidins and several other constituents. See Boralle, N., et al., In: Ginkgolides, Chemistry, Biology, Pharmacology and Clinical perspectives, Ed: Braquet, P., J.R. Prous Science Publishers, 1988.
  • the present invention is directed to a method of establishing a gene regulation profile of a Gingko biloba extract or a component of the Ginkgo biloba extract, which comprises the steps of: obtaining at least one batch of untreated cells; treating a first batch of cells with an extract of Ginkgo biloba or a component of the Ginkgo biloba extract to obtain a treated batch of cells; quantifying an affect on the expression of one or more genes of the treated cells to obtain a quantity of affected genes; and comparing the quantity of affected genes with a quantity of genes of cells not treated with Ginkgo biloba or a component of the Ginkgo biloba extract to obtain the gene regulation profile of the Ginkgo biloba extract or a component of the Ginkgo biloba extract.
  • a preferred method of the foregoing method is where the quantifying step comprises: isolating poly A+ RNA from the treated batch of cells to obtain treated poly A+ RNA; isolating poly A+ RNA from a batch of untreated cells to obtain untreated poly A+ RNA; generating labeled cDNA probes from the treated poly A+ RNA to obtain treated labeled cDNA probes; generating labeled cDNA probes from the untreated poly A+ RNA to obtain untreated labeled cDNA probes; hybridizing the treated cDNA probes to an array having one or more cDNA to obtain a treated hybridized array of cDNA; hybridizing the untreated cDNA probes to an array having one or more cDNA to obtain an untreated hybridized array of cDNA; quantifying each of the cDNA of the treated hybridized array of cDNA to obtain quantities of treated cDNA; quantifying each of the cDNA of the untreated hybridized array of cDNA to obtain quantities of untreated cDNA; and comparing
  • MDA-231 cells the Ginkgo biloba extract is EGB 761®; and the array is a gene chip having multiple genes.
  • a preferred method of the immediately foregoing method is where the gene regulation profile of EGB 761® comprises increased expression of c-Myc protooncogene, and decreased expression of the following genes: prothymosin- ⁇ ,
  • CDK2 CDK2, p55CDC, myeloblastin p120 proliferating-cell nuclear antigen, NET1, ERK2,
  • CDK2 -83%
  • TRADD -51%
  • B-lymphocyte Antigen -62%
  • L1CAM -72%
  • ⁇ -catenin -58%
  • Integrin Subunit ⁇ M -41%
  • Integrin Subunit ⁇ 5 -55%
  • CSF-1 Macrophage Colony-stimulating Factor-1
  • Heparin-binding EGF-like Growth Factor (HB-EGF) -62%
  • HGFLP Hepatocyte Growth Factor-like Protein
  • the present invention provides a method of verifying the identity of a Ginkgo biloba extract which comprises the steps of: obtaining a gene regulation profile of the Gingko biloba extract to obtain a gene regulation profile; obtaining a gene regulation profile of EGB 761® to yield an EGB 761® gene regulation profile; comparing the gene regulation profile of the Gingko biloba extract with the EGB
  • a preferred method of the immediately foregoing method is where the method of obtaining a gene regulation profile of the Ginkgo biloba extract and the EGB 761® gene regulation profile comprises the steps of: isolating poly A+ RNA from the treated batch of cells to obtain treated poly A+ RNA; isolating poly A+ RNA from a batch of untreated cells to obtain untreated poly A+ RNA; generating labeled cDNA probes from the treated poly A+ RNA to obtain treated labeled cDNA probes; generating labeled cDNA probes from the untreated poly A+ RNA to obtain untreated labeled cDNA probes; hybridizing the treated cDNA probes to an array having one or more cDNA to obtain a treated hybridized array of cDNA; hybridizing the untreated cDNA probes to an array having one or more cDNA to obtain an untreated hybridized array of cDNA; quantifying each of the cDNA of the treated hybridized array of cDNA to obtain quantities of treated cDNA; quantifying each
  • ginkgo terpenoid includes all of the naturally occurring terpenes which are derived from the gymnosperms tree Ginkgo biloba as well as synthetically produced ginkgo terpenoids and pharmaceutically active derivatives and salts thereof and mixtures thereof.
  • examples of ginkgo terpenoids include ginkgolides.
  • Examples of ginkgo terpenoids are disclosed in Ginkgolides, Chemistry, Biology, Pharmacology, and Clinical Perspectives, J.R. Provs. Science Publishers, Edited by P. Braguet (1988); F.V. DeFeudis, Ginkgo Biloba Extract (EGB 761®); Pharmacological Activities and Clinical Applications, Elsevier, Chapter II (1991).
  • ginkgolide as used herein include the various ginkgolides disclosed in the books cited above as well as non-toxic pharmaceutically active derivatives thereof.
  • examples of ginkgolide derivatives include tetrahydro derivatives, acetyl derivatives, and alkyl esters such as the monoacetate derivatives and triacetate derivatives disclosed in Okabe, et al., J. Chem. Soc. (c), pp. 2201-2206 (1967).
  • Ginkgolide B has the following structure and as used herein, refers to isolated ginkgolide B:
  • Ginkgo biloba extract includes a collection of natural molecules, including terpenoids, derived from the leaves of the Ginkgo biloba tree.
  • the extract is the specific formulation of Ginkgo biloba extract known as EGB 761®.
  • a gene expression profile of an extract of Ginkgo biloba or a component thereof can be obtained by methods known in the art. Traditionally such a profile was obtained by RNA Northern blot analysis or ribonuclease protection assay for each individual gene product. However, these assays were time consuming and took about 2-3 days to analyze each gene. Currently a gene expression profile can be established through the utilization of nucleic acid array technology such as the Atlas human cDNA expression array I from Clontech (Palo Alto, CA); GeneFilters Microarrays by Research Genetics (Huntsville, AL); and the Gene Expression Microarrays by Genome Systems, Inc. (St. Louis, MO).
  • nucleic acid array technology such as the Atlas human cDNA expression array I from Clontech (Palo Alto, CA); GeneFilters Microarrays by Research Genetics (Huntsville, AL); and the Gene Expression Microarrays by Genome Systems, Inc. (St. Louis, MO).
  • the Gene Filters Microarray are high density DNA arrays produced on 5 cm x 7 cm membranes. At present there are four membranes available for human genes and one for rat genes. Each membrane contains approximately 5,000 sequences. Some of these sequences are known genes, while most sequences represent ESTs of unknown function. Research Genetics will soon make available gene arrays on the Affymetrix Gene chip platform, where the genes are immobilized on a silicon chip. In the case of silicon chips, the hybridization results (with the mRNA of choice) are detected by fluorescence and analyzed by pattern recognition compared to either fluorescence or radioactivity that can be used for the detection of the hybridization results in the membrane arrays.
  • Genome System's method utilizes the GEM technology where a collection of complementary DNA (cDNA) molecules that contain the genetic information from the biological systems of interest are deposited and bonded on a glass surface in an array format. Next, large portions from one half of the DNA's double strand are removed, thus activating the individual elements of the array, preparing them to react with their uniquely matched DNA counterparts in the cells being tested.
  • GEM technology can fit 10,000 unique genes on a single array. GEM technology also uses a color coded technique to examine the difference in expression between two mRNA samples.
  • An array of cDNA will contain numerous animal, such as rat or human, preferably human, PCR-amplified cDNA fragments immobilized on a positively charged nylon membrane or a glass slide or a silicon chip or any other surface to be developed where a DNA/matrix interaction is allowed.
  • a cell type of interest is treated with and without a Ginkgo biloba extract or a component thereof for about 48 hours.
  • Poly A+ RNA is isolated from control and extract-treated cells.
  • 32 P-labeled, fluorescent, chemiluminescent or colorimetric cDNA probes, preferably fluorescent or colorimetric labeling when using glass or silicon chip arrays, are generated from each poly A+RNA and hybridized to the array according to the manufacturer's recommendations.
  • Autoradiography is performed by exposing the blots to film at about -70°C for 4-96 hr. Quantification of the hybridization is carried out using an imaging system, which can detect the fluorescence or chemiluminesence then capture the image and analyze the data, such as the SigmaGel software. Multiple exposures are used in order to detect genes expressed at low levels.
  • the three internal controls, ubiquitin, G3PDH and ⁇ - actin are used to compare the relative expression levels of the detected gene products in the control and the extract-treated cells. Experimental variations are corrected using the ratios of gene expression versus the internal controls. The effect of the extract treatment on each gene product is expressed as % of control (untreated) cells.
  • the Atlas human cDNA expression array I from Clontech contains 588 human PCR-amplified cDNA fragments of 200-500 bp long immobilized on a positively charged nylon membrane.
  • MDA-231 cells were treated with and without 20 ⁇ g/ml EGB 761® for 48 hours.
  • Poly A+ RNA was isolated from control and EGB 761 ⁇ -treated cells.
  • 32 P-labeled cDNA probes were generated from each poly A+RNA and hybridized to the Atlas array according to the manufacturer's recommendations.
  • Table I shows genes affected consistently, at a level above 30% of control, by the EGB 761® treatment.
  • Table I shows that the treatment increased the expression of the c-Myc protooncogene and decreased the expression of 35 gene products, including oncogenes (AP-1, PE-1, RhoA, n-Myc), cell cycle regulators (CDK2, p55CDC, PCNA p120), signal transduction modulators (NET1, ERK2), apoptosis- related products (SGP-2, NIP1) receptors (A2A, RXR-beta, Grb2), transcription factors (ld-2, ATF-4, ETR101, ETR-103), growth factors (HB-EGF, HGF-like), and cell adhesion molecules (CD19, L1CAM, integrins ⁇ 3, ⁇ 4, ⁇ 6, ⁇ 5, Mac-1, ⁇ -catenin) which are directly involved in various pathways regulating cell proliferation.
  • oncogenes AP-1, PE-1, RhoA, n-
  • Gene expression profiles can be established for Ginkgo biloba extracts of known origin and then can be compared with the gene expression profile of Ginkgo biloba extracts of unknown origin or extracts that purport to be a certain commercial extract. The comparison of the profiles can thus be used as a screening means to authenticate the origin of an extract.
  • CDK2 -83% -cyclin-dependent tyrosine kinase involved in progression through the (49) cell cycle
  • ERK2 -46% -member of the extracellular signal-related protein kinase family (52)
  • Antigen -expression is down-regulated during retinoid-inhibition of lymphoblastoid B-cell proliferation
  • L1 CAM expression is associated with high-grade migration of glioma cells ⁇ -catenin -58% -involved in cadherin-mediated cell-cell interactions (74)
  • Macrophage Colony- -31% -regulates the proliferation, differentiation, and survival of monocytes, (83) stimulating Factor-1 macrophages and their precursors (84)
  • CSF-1 -initiates a mitogenic signal that is required throughout G1 phase -CSF-1 stably transfected ovarian granulosa cells exhibit enhanced cell proliferation
  • HB-EGF Growth Factor
  • HGFLP human keratinocytes lnhibin ⁇ -69% -a member of the inhibin family of heterodimeric growth factors (88) -inhibin ⁇ is a marker of trophoblastic neoplasia and is highly (89) expressed in virilizing adenomas
  • FADD/MORT1 A dominant interfering mutant of FADD/MORT1 enhances deletion of autoreactive thymocytes and inhibits proliferation of mature T lymphocytes.
  • Atf4 suppresses c-Ha-ras oncogene transcript levels and cellular transformation in
  • prognostic significance of proliferation-associated nucleolar protein p120 expression in prostate adenocarcinoma A comparison with cyclins A and B1, Ki-67, proliferating cell nuclear antigen, and p34(cdc2). Cancer, 85: 1569-1576, 1999.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Analytical Chemistry (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Biotechnology (AREA)
  • Physics & Mathematics (AREA)
  • Biochemistry (AREA)
  • Microbiology (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Peptides Or Proteins (AREA)
EP01920817A 2000-03-31 2001-03-27 Verfahren zum nachweis von ginko biloba in pflanzenextrakten durch bestimmung des genprofils Withdrawn EP1292706A2 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US19388900P 2000-03-31 2000-03-31
US193889P 2000-03-31
PCT/US2001/009832 WO2001075181A2 (en) 2000-03-31 2001-03-27 Method of identifying ginko biloba in a plant extract by gene profiling

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EP1292706A2 true EP1292706A2 (de) 2003-03-19

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EP01920817A Withdrawn EP1292706A2 (de) 2000-03-31 2001-03-27 Verfahren zum nachweis von ginko biloba in pflanzenextrakten durch bestimmung des genprofils

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EP (1) EP1292706A2 (de)
JP (1) JP2003529377A (de)
KR (1) KR100479151B1 (de)
CN (1) CN1185354C (de)
AU (2) AU2001247832B2 (de)
CA (1) CA2403303A1 (de)
CZ (1) CZ20023275A3 (de)
HK (1) HK1053150A1 (de)
HU (1) HUP0301997A3 (de)
IL (1) IL151856A0 (de)
MX (1) MXPA02009412A (de)
NO (1) NO20024611L (de)
NZ (1) NZ521728A (de)
PL (1) PL365418A1 (de)
RU (1) RU2271393C2 (de)
WO (1) WO2001075181A2 (de)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020018989A1 (en) * 1996-11-07 2002-02-14 Albert Beaufour Method of identifying pharmaceuticals from plant extracts
CN102869776B (zh) * 2009-12-23 2017-06-23 库尔纳公司 通过抑制肝细胞生长因子(hgf)的天然反义转录物而治疗hgf相关疾病
CN109694903A (zh) * 2019-01-09 2019-04-30 中国药科大学 基于银杏内酯含量与基因表达关联分析筛选银杏内酯合成关键基因的方法

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WO1999037817A1 (en) * 1998-01-26 1999-07-29 Schering Aktiengesellschaft Gene expression methods for screening compounds

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Title
See references of WO0175181A2 *

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Publication number Publication date
CN1185354C (zh) 2005-01-19
CZ20023275A3 (cs) 2003-03-12
HK1053150A1 (zh) 2003-10-10
MXPA02009412A (es) 2005-02-03
WO2001075181A3 (en) 2002-11-07
NO20024611D0 (no) 2002-09-26
NO20024611L (no) 2002-11-19
AU2001247832B2 (en) 2005-07-21
KR20020089409A (ko) 2002-11-29
PL365418A1 (en) 2005-01-10
NZ521728A (en) 2004-10-29
CA2403303A1 (en) 2001-10-11
HUP0301997A3 (en) 2005-11-28
AU4783201A (en) 2001-10-15
IL151856A0 (en) 2003-04-10
HUP0301997A2 (hu) 2003-09-29
KR100479151B1 (ko) 2005-03-28
RU2271393C2 (ru) 2006-03-10
WO2001075181A2 (en) 2001-10-11
CN1439059A (zh) 2003-08-27
JP2003529377A (ja) 2003-10-07

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