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WO2000070085A2 - Procede pour determiner l'effet de differents agents chimiotherapeutiques et/ou d'une radiotherapie sur des affections malignes, et procede de selection d'agents therapeutiques actifs pour le traitement de ces affections - Google Patents

Procede pour determiner l'effet de differents agents chimiotherapeutiques et/ou d'une radiotherapie sur des affections malignes, et procede de selection d'agents therapeutiques actifs pour le traitement de ces affections Download PDF

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Publication number
WO2000070085A2
WO2000070085A2 PCT/DE2000/001444 DE0001444W WO0070085A2 WO 2000070085 A2 WO2000070085 A2 WO 2000070085A2 DE 0001444 W DE0001444 W DE 0001444W WO 0070085 A2 WO0070085 A2 WO 0070085A2
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WO
WIPO (PCT)
Prior art keywords
therapy
bax
genes
mutations
expression
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/DE2000/001444
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German (de)
English (en)
Other versions
WO2000070085A3 (fr
Inventor
Peter Daniel
Timo Hillebrand
Bernd DÖRKEN
Peter Bendzko
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.)
THERAGEN MOLEKULARMEDIZINISCHE INFORMATIONSSYSTEME AG
Original Assignee
THERAGEN MOLEKULARMEDIZINISCHE INFORMATIONSSYSTEME 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 THERAGEN MOLEKULARMEDIZINISCHE INFORMATIONSSYSTEME AG filed Critical THERAGEN MOLEKULARMEDIZINISCHE INFORMATIONSSYSTEME AG
Priority to EP00941910A priority Critical patent/EP1181394A2/fr
Priority to AU56720/00A priority patent/AU5672000A/en
Publication of WO2000070085A2 publication Critical patent/WO2000070085A2/fr
Publication of WO2000070085A3 publication Critical patent/WO2000070085A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • 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
    • 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

Definitions

  • the invention relates to a method for detecting the effect of different chemotherapeutic agents and / or radiation therapy in malignant diseases, the expression profiles of tumor and / or cell growth and / or apoptosis-associated genes and / or the individual differences (mutations) in the Gene sequences can be determined. Changes in connection with chemotherapeutic agents and / or radiation therapy are identified, represented and diagnosed. Furthermore, the invention relates to a method for selecting effective therapeutic agents for the treatment of malignant diseases. The status of cell cycle genes and / or of apoptosis-associated target genes or of their gene products in body fluids, cells and / or organs is determined and their effects on corresponding therapeutic agents are evaluated diagnostically. In a preferred embodiment, Bax and p53 expression or mutations are examined, and information derived therefrom for individual-specific therapy decisions in leukemic diseases and other tumor diseases is provided.
  • the process of a malignant change in a cell begins very early, often with just a single change in the genetic material. It runs through various stages up to the degenerated cell and is not yet finished even at this stage.
  • the object of the invention was therefore to use knowledge at the molecular level for an individual-specific tumor therapy and to find an effective selection of therapeutic agents for the patients concerned in order to enable effective treatment.
  • Tumor development, tumor progression and resistance to therapy are determined by cell cycle and apoptosis regulating factors.
  • the basis of the present invention was the surprising finding that by determining their expression profile this tumor or.
  • an effective and promising form of therapy for the patient can be derived from this.
  • the invention therefore relates to a method for detecting the effect of different chemotherapeutic agents and / or radiation therapy in the case of malignant diseases.
  • the expression profiles of tumor and / or cell growth-associated genes and / or the individual differences (mutations) in the gene sequences are determined and interactions (correlations) with chemotherapeutic agents and / or radiation therapy are identified, represented and diagnostically evaluated.
  • the expression profiles and / or mutations of the said genes are preferably determined by means of protein or DNA / RNA analysis.
  • the expression profiles and / or mutations of the respective individual genes are evaluated.
  • the profiles and / or mutations of different genes can also be combined, whereby the creation of an individual therapy scheme is improved and an individual prognosis and risk assessment is possible.
  • the expression profiles of Bax, p53, pl6, caspase and / or Rb genes or their mutations are preferably used and evaluated for diagnosis.
  • the status of p53 genes and of Bax genes or of their gene products is particularly preferably identified.
  • the invention relates in particular to a method for selecting effective therapeutic agents for the treatment of malignant diseases. It is characterized by determining the status of cell cycle genes and / or apoptosis-associated target genes or their gene products ex vivo in body fluids, cells and organs, which is evaluated diagnostically in connection with the action of appropriate therapeutic agents.
  • Therapeutic agents in the sense of the invention are known agents for the therapy of leukemic or lymphoma diseases and other malignant diseases, such as e.g. tumors of the gastrointestinal tract, pancreas, prostate, gynecological tumors (such as ovaries, cervix, breast), sarcomas, brain tumors, tumors of the skin and lungs, and tumors of endocrine organs, such as the thyroid gland
  • cytostatics preferably steroid hormones (e.g. prednisone, prednisolone, methylprednisolone, and other glucocorticoids), antimetabolites (cladribine (2-CDA), fludarabine, mercaptopurine, arabinoside C, 5-substituted dideoxynucleosides, such as 5-fluorouracil, azidothymidine) to alkylants (e.g. mafosfamide, chlorambucil, melphalan, cyclophosphamide), taxanes (such as paclitaxel, docetaxel), anthracyclines (e.g.
  • idarubicin doxorubicin, epirubicin, mitoxanthrons
  • topos-isomerase topos-isomerase
  • Vinca alkaloids (vincristine, vinblastine, vinorelbine), cis-platinum and other platinum analogues u. v. a. m. as well as radiation therapy.
  • CLL chronic lymphoblastic leukemia
  • an individualized form of therapy can be applied via the combined diagnosis of the two candidate genes p53 and Bax by creating individual therapy schemes by combining the genetic status of the p53 and Bax genes or their gene products and / or mutations.
  • the invention further relates to the use of the status determination of cell cycle genes and / or of apoptosis-associated target genes or of their gene products or mutations by means of protein or DNA / RNA analysis for determining therapy resistance and for the targeted selection of therapeutic agents for cytotoxic therapies.
  • the analysis is preferably carried out using Bax expression or mutations or using p53 expression or mutations.
  • the status determination of Bax and p53 genes is particularly preferably used for risk-adapted tumor therapy in leukemic diseases, such as CLL and other tumors.
  • leukemic diseases such as CLL and other tumors.
  • the use is made in combination of p53 and Bax with further cell cycle and apoptosis regulators, which can also be used either alone or in combination as a molecular pathway (signal path) diagnosis in malignant tumors or precancerous diseases .
  • the present investigations were carried out as examples for the tumor suppressor protein p53 and the proapoptotic gene Bax in patients with chronic lymphoblastic leukemia (CLL). Further data are e.g. B. also for these and other apoptosis and cell cycle regulators before in tumors of the gastrointestinal tracts, such as gastric carcinoma, esophageal carcinoma and sarcomas.
  • the two apoptosis-influencing proteins p53 and Bax were able to provide conclusive evidence that diagnostic characterization of corresponding tumor genes at the molecular level (DNA) and at the expression level (protein) makes it possible to selectively select cytostatics, and thus to achieve improved treatment.
  • the findings on the molecular pathogenesis and resistance to therapy of tumors can, according to the invention, be used as the basis for an individual-specific tumor therapy and in this way achieve a more targeted treatment and ultimately a maximum success for the affected patient.
  • the invention makes it possible to use changed cellular tumor markers as a decision criterion for the selection of different standard chemotherapeutic agents, i.e. also to take advantage of positive correlations between changed tumor markers and the effectiveness or ineffectiveness of chemotherapy drugs. This offers the possibility, for the first time after a characterization of selected cellular tumor markers, to selectively select the form of the chemotherapeutic agent to be used or also a radiation therapy or a combination thereof.
  • Figure 2 shows the correlation between Bax expression and the LC90 dose of doxorubicin in 37 CLL patients.
  • Figure 3 shows the reduced cytostatics sensitivity of CLL cells in vitro against the alkylating agents chlorambucil and melphalan as well as against fludarabine in p53-mutated CLL patients compared to the p53 wild type.
  • the p53 mutations were determined by means of SSCP-PCR for exons 5 to 8.
  • the bar height corresponds to the dose of the cytostatic in ⁇ g / ml.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Analytical Chemistry (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Biophysics (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biotechnology (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Physics & Mathematics (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un procédé permettant de déterminer l'effet de différents agents chimiothérapeutiques et/ou d'une radiothérapie sur des affections malignes, selon lequel on définit les profils d'expression de gènes associés à des tumeurs et/ou à la croissance cellulaire et/ou à l'apoptose et/ou les différences (mutations) individuelles dans les séquences de ces gènes. Des modifications liées à l'utilisation des agents chimiothérapeutiques et/ou de la radiothérapie sont identifiées, représentées et soumises à une évaluation diagnostique. L'invention concerne en outre un procédé permettant de sélectionner des agents thérapeutiques efficaces pour le traitement d'affections malignes. L'état de gènes impliqués dans le cycle cellulaire et/ou le gène cible associé à l'apoptose ou de produits géniques de ceux-ci dans des liquides corporels, des cellules et/ou des organes est déterminé et des agents thérapeutiques correspondants sont évalués du point de vue diagnostic en ce qui concerne leur effet. Dans un mode de réalisation préféré, l'expression des gènes bax et p53 ou leurs mutations sont examinées et les informations qui en découlent sont utilisées pour la prise de décision thérapeutique concernant spécifiquement un individu souffrant d'une leucémie ou d'une autre affection maligne.
PCT/DE2000/001444 1999-05-14 2000-05-10 Procede pour determiner l'effet de differents agents chimiotherapeutiques et/ou d'une radiotherapie sur des affections malignes, et procede de selection d'agents therapeutiques actifs pour le traitement de ces affections Ceased WO2000070085A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP00941910A EP1181394A2 (fr) 1999-05-14 2000-05-10 Procede pour determiner l'effet de differents agents chimiotherapeutiques et/ou d'une radiotherapie sur des affections malignes, et procede de selection d'agents therapeutiques actifs pour le traitement de ces affections
AU56720/00A AU5672000A (en) 1999-05-14 2000-05-10 Method for detecting the effect of different chemotherapeutic agents and/or radiation therapy in malignant diseases and method for selecting more effective therapeutic agents for the therapy thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19922052.2 1999-05-14
DE19922052A DE19922052A1 (de) 1999-05-14 1999-05-14 Verfahren zum Nachweis der Wirkung von unterschiedlichen Chemotherapeutika und/oder einer Strahlentherapie bei malignen Erkrankungen sowie Verfahren zur Auswahl wirkungsvoller therapeutischer Mittel zu deren Therapie

Publications (2)

Publication Number Publication Date
WO2000070085A2 true WO2000070085A2 (fr) 2000-11-23
WO2000070085A3 WO2000070085A3 (fr) 2001-08-09

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PCT/DE2000/001444 Ceased WO2000070085A2 (fr) 1999-05-14 2000-05-10 Procede pour determiner l'effet de differents agents chimiotherapeutiques et/ou d'une radiotherapie sur des affections malignes, et procede de selection d'agents therapeutiques actifs pour le traitement de ces affections

Country Status (4)

Country Link
EP (1) EP1181394A2 (fr)
AU (1) AU5672000A (fr)
DE (1) DE19922052A1 (fr)
WO (1) WO2000070085A2 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005100606A3 (fr) * 2004-04-09 2006-06-22 Genomic Health Inc Marqueurs d'expression genique permettant de predire la reponse a la chimiotherapie
EP2474625A1 (fr) * 2011-01-05 2012-07-11 Daniela Kandioler Prédiction de la réponse dans le traitement du cancer
WO2012093155A1 (fr) 2011-01-05 2012-07-12 Daniela Kandioler Prédiction d'une réponse dans le traitement du cancer (thérapie anticancéreuse adaptée à p53)
US9292660B2 (en) 2006-05-18 2016-03-22 Caris Mpi, Inc. Molecular profiling of tumors
US9372193B2 (en) 2006-05-18 2016-06-21 Caris Mpi, Inc. System and method for determining individualized medical intervention for a disease state
WO2022216725A1 (fr) * 2021-04-05 2022-10-13 Brown University Procédés d'optimisation du traitement du cancer colorectal

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8624027B2 (en) 2005-05-12 2014-01-07 Abbvie Inc. Combination therapy for treating cancer and diagnostic assays for use therein

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0988398A4 (fr) * 1997-05-21 2005-05-18 Clontech Lab Inc Ensembles d'acide nucleique

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005100606A3 (fr) * 2004-04-09 2006-06-22 Genomic Health Inc Marqueurs d'expression genique permettant de predire la reponse a la chimiotherapie
US7871769B2 (en) 2004-04-09 2011-01-18 Genomic Health, Inc. Gene expression markers for predicting response to chemotherapy
US9605318B2 (en) 2004-04-09 2017-03-28 Genomic Health, Inc. Gene expression markers for predicting response to chemotherapy
US9292660B2 (en) 2006-05-18 2016-03-22 Caris Mpi, Inc. Molecular profiling of tumors
US9322067B2 (en) 2006-05-18 2016-04-26 Caris Mpi, Inc. Molecular profiling of tumors
US9372193B2 (en) 2006-05-18 2016-06-21 Caris Mpi, Inc. System and method for determining individualized medical intervention for a disease state
US9383365B2 (en) 2006-05-18 2016-07-05 Caris Mpi, Inc. System and method for determining individualized medical intervention for a disease state
US9389234B2 (en) 2009-02-11 2016-07-12 Caris Mpi, Inc. Molecular profiling of tumors
EP2474625A1 (fr) * 2011-01-05 2012-07-11 Daniela Kandioler Prédiction de la réponse dans le traitement du cancer
WO2012093155A1 (fr) 2011-01-05 2012-07-12 Daniela Kandioler Prédiction d'une réponse dans le traitement du cancer (thérapie anticancéreuse adaptée à p53)
WO2012093152A1 (fr) 2011-01-05 2012-07-12 Daniela Kandioler Prédiction d'une réponse dans le traitement du cancer
WO2022216725A1 (fr) * 2021-04-05 2022-10-13 Brown University Procédés d'optimisation du traitement du cancer colorectal

Also Published As

Publication number Publication date
DE19922052A1 (de) 2000-11-16
WO2000070085A3 (fr) 2001-08-09
EP1181394A2 (fr) 2002-02-27
AU5672000A (en) 2000-12-05

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