WO2009021551A1 - Procédé d'évaluer du risque de toxicité d'une chimiothérapie - Google Patents

Procédé d'évaluer du risque de toxicité d'une chimiothérapie Download PDF

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Publication number
WO2009021551A1
WO2009021551A1 PCT/EP2007/058349 EP2007058349W WO2009021551A1 WO 2009021551 A1 WO2009021551 A1 WO 2009021551A1 EP 2007058349 W EP2007058349 W EP 2007058349W WO 2009021551 A1 WO2009021551 A1 WO 2009021551A1
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cda
chemotherapeutic agent
activity
risk
gemcitabine
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PCT/EP2007/058349
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English (en)
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Joseph Ciccolini
Cédric Mercier
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Universite De La Mediterranee
Assistance Publique Hôpitaux De Marseille
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Priority to PCT/EP2007/058349 priority Critical patent/WO2009021551A1/fr
Publication of WO2009021551A1 publication Critical patent/WO2009021551A1/fr

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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
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5014—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing toxicity
    • 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
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/978—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention relates to the field of cancer treatments. More particularly, it provides a method for determining the risk of toxicity upon a chemotherapeutic agent intake in patients afflicted with a cancer.
  • Gemcitabine is an antimetabolite drug used in the treatment of various solid tumors, including lung, pancreatic, or gynaecological cancers.
  • innovative combinational strategies e.g. gemcitabine + capacitabine (Gemcap), or gemcitabine + oxaliplatin (Gemox)
  • gemcitabine is characterized by a narrow therapeutic index and its liver elimination depends upon a key enzymatic step, driven by cytidine deaminase (CDA).
  • CDA cytidine deaminase
  • the inventors now propose to detect patients with abnormal CDA activity by phenotyping them prior to the administration of a chemotherapeutic agent such as gemcitabin.
  • An object of the invention is thus an in vitro method for determining the risk of toxicity upon a chemotherapeutic agent intake in a patient afflicted with a cancer, wherein metabolism of the chemotherapeutic agent involves cytidine deaminase (CDA), which method comprises determining the CDA activity in a biological sample of the patient, wherein an alteration in CDA activity compared to a control value is indicative of a risk of toxicity upon the chemotherapeutic agent intake.
  • CDA cytidine deaminase
  • metabolism of the chemotherapeutic agent means in particular liver elimination of the chemotherapeutic agent or in vivo activation of the chemotherapeutic agent, i.e., in vivo conversion of the pro-drug into a pharmacologically active drug.
  • the chemotherapeutic agent is gemcitabine.
  • this method can be fully used for example either to detect patients with impaired CDA activity, at risk of severe toxicities with Ara-C, CNDAC, decitabine and/or tezacitabine intake, or, conversely, to detect patients displaying an abnormal increase of the CDA activity ("extensive activity") compared to a control value, at risk of severe toxicities with capecitabine and/or DMDC intake.
  • the CDA activity may be determined by radioactive High Performance Liquid Chromatography (HPLC), or by visible spectrophotometry.
  • HPLC Radioactive High Performance Liquid Chromatography
  • the CDA activity is advantageously determined by visible spectrophotometry.
  • kits for determining the risk of toxicity upon a chemotherapeutic agent intake in a patient afflicted with a cancer wherein liver elimination of the chemotherapeutic agent or in vivo activation of the chemotherapeutic agent involves cytidine deaminase (CDA), which kit comprises : a container comprising cytidine; a container comprising ammonium; - a leaflet which describes a method for determining the CDA activity in a biological sample, by measuring the amount of ammonium released through conversion of cytidine into uridine by spectrophotometry, wherein the leaflet indicates that a CDA activity inferior to about 1 U/mg is indicative of a risk of a severe toxicity upon intake of a chemotherapeutic agent the liver elimination of which involves CDA, such as gemcitabine, Ara-C, CNDAC, decitabine and/or tezacitabine, whereas a CDA activity superior to 8 U/mg
  • CDA such as gemcita
  • Figure 1 shows distribution of seric CDA activities in 45 reference patients without toxicities upon gemcitabine exposure, and comparison with the CDA activity measured in the patient with fatal outcome.
  • Figure 2 shows High-resolution melting analysis of CDA single nucleotide polymorphisms 79A>C, 208G>A and 435C>T. Genomic DNA from reference patients were used for PCR and post-PCR melting curve analysis carried out on a LightCycler®480 instrument. Wild-type DNA was used as reference for each allele.
  • the inventors have developed a method to determine phenotypically CDA status in cancer patients, more particularly as an attempt to detect those at risk upon gemcitabine, Ara-C, CNDAC, decitabine, tezacitabine, capecitabine and/or DMDC intake. Conjointly to genotypic investigations, this method was used to phenotype, in a retrospective setting, a female patient displaying extremely severe, and eventually lethal, toxicities after administration of a standard gemcitabine/carboplatin protocol. The phenotypic investigation showed a marked CDA deficiency (-75%) in this patient when compared with a reference, non-toxic population.
  • Patients displaying an abnormal CDA phenotype may be patients displaying a deficient CDA activity at risk upon administration of gemcitabine, and/or of chemotherapeutic agents the metabolism and liver detoxification of which are similar to those of gemcitabine, such as Ara-C, CNDAC, decitabine and tezacitabine.
  • Other patients displaying an abnormal CDA phenotype may be patients displaying an extensive CDA activity at risk upon administration of capecitabine, and/or of chemotherapeutic agents the metabolism and in vivo activation (conversation of a pro-drug into a drug) of which are similar to those of capecitabine, such as DMDC.
  • the method of the invention comprises determining the level of CDA activity in a cancer patient who is to receive a chemotherapy, and comparing it to a control value.
  • An alteration in the CDA activity compared to the control value is indicative of a toxicity upon administration of the chemotherapeutic agent, the metabolism of which involves CDA.
  • alteration means that CDA does not show a normal activity, compared to a control value.
  • control value may be the CDA activity of a reference non-toxic population.
  • the reference population does not show any mutation in the CDA gene that is known to modify the activity of the gene product.
  • the control value may be a cut-off value as indicated below.
  • the cut-off value is expressed in CDA activity unit per milligram of sample total protein (U/mg).
  • the alteration is a deficiency in CDA activity, or in other words, an abnormally decreased CDA activity compared to a control value.
  • the alteration is a CDA extensive activity, or in other words, an abnormally increased (or extensive) CDA activity compared to a control value.
  • Gemcitabine (marketed as Gemzar®) is 2'-deoxy-2',2'-difluorocytidine.
  • a CDA activity, in a serum sample, inferior to a control value of about 1 U/mg is abnormal and indicative of a risk of severe toxicity upon gemcitabine uptake.
  • the chemotherapeutic agent is selected from the group consisting of cytarabine (also known as Ara-C), CNDAC, decitabine and tezacitabine.
  • Cytarabine is 4-amino-1-beta-D-arabinofuranosyl-2(1 H)-pyrimidinone.
  • CNDAC is 2'-C-cyano-2'-deoxy-1-beta-D-arabinofuranosylcytosine.
  • Tezacitabine is (E)-2'-deoxy-2'-(fluoromethylene)cytidine.
  • Ara-C, CNDAC, decitabine and tezacitabine are anti-metabolite agents.
  • a CDA activity, in a serum sample, inferior to a control value of about 1 U/mg is abnormal and indicative of a risk of severe toxicity upon Ara-C, CNDAC, decitabine and/or tezacitabine uptake.
  • the chemotherapeutic agent is selected from the group consisting of capecitabine and/or DMDC.
  • Capecitabine (marketed as Xeloda®) is pentyl[1-(3,4-dihydroxy-5-methyl- tetrahydrofuran-2-yl)- 5-fluoro-2-oxo-1 H-pyrimidin- 4-yl]aminomethanoate.
  • capecitabine follows a pathway with three enzymatic steps and two intermediary metabolites, 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5- fluorouridine (5'-DFUR), to form 5-fluorouracil.
  • Capecitabine can trigger toxicity due to its liver transformation into 5-fluorouracil in patients displaying an abnormal increase of the CDA activity compared to a control value (extensive CDA activity).
  • a CDA activity, in a serum sample, superior to a control value of about 8U/mg is abnormal and indicative of a risk of severe toxicity upon capecitabine uptake.
  • DMDC is a chemotherapeutic agent the metabolism and in vivo activation (conversation of a pro-drug into a drug) of which is similar to those of capecitabine.
  • DMDC is 2'-deoxy-2'-methylidenecytidine.
  • a CDA activity, in a serum sample, superior to a control value of about 8U/mg is abnormal and indicative of a risk of severe toxicity upon DMDC uptake.
  • the term « severe toxicity » refers to a grade 3 toxicity or higher according to standard WHO grading (see Reporting Guidelines of the National Cancer Institute - http://ctep.cancer.gov/reporting/ctc.html).
  • Toxicity is of a grade 3 when said toxicity causes haematological disorders (e.g., leucopoenia, thrompopenia, anaemia, pancytopenia) and subsequent infectious diseases (such as fever, sepsis) and digestive diseases (such as diarrhoea, mucitis, nausea or vomiting).
  • Toxicity of the highest grade (grade 5) causes death of the patient.
  • Such a severe toxicity means that the chemotherapeutic agent is not suitable for the tested patient and may be life-threatening. Therefore, most preferably, the method of the invention should be performed in a patient before the chemotherapeutic agent is prescribed. The dosage regimen should then be adapted to the risk of severe toxicity herein determined or another chemotherapeutic agent which does not involve CDA for kidney elimination, should be chosen instead.
  • the CDA activity is determined by spectrophotometry, preferably by visible spectrophotometry, most preferably at 630nm.
  • the CDA activity may be determined by measuring the amount of ammonium released through conversion of cytidine into uridine, by spectrophotometry.
  • the CDA activity is determined by: a. incubating the biological sample with cytidine; b. setting up a calibration curve of ammonium to be incubated similarly with the sample; c. precipitating proteins so as to stop the reaction ; d. centrifuging and recovering the upper layer; e. incubating the recovered upper layer of step d) with a mixture of phenol and sodium hypochlorite and recovering the upper layer comprising the ammonium; f. detecting ammonium in the recovered upper layer of step e) with a spectrophotometer, preferably at 630nm; g. calculating the CDA activity, in regard with the signahactivity relationship generated by the calibration curve and the amount of proteins in the sample.
  • the protein amount of the sample is measured before incubating the sample with cytidine. For each patient, one additional sample is incubated without the substrate (blank).
  • the biological sample may be a body fluid, such as serum, plasma, and blood. It may also be a tissue biopsy, in particular a liver biopsy. Preferably, the biological sample is serum.
  • the patient is any human adult or child afflicted with a cancer, for the treatment of which chemotherapy is needed.
  • Solid tumors that may benefit from gemcitabine include lung, pancreatic, bladder and breast cancers.
  • Cancers that may benefit from Ara-C include acute myeloid leukemia, chronic myeloid leukemia, acute lymphoid leukemia, lymphomas.
  • Cancers that may benefit from capecitabine include digestive cancers, in particular colorectal cancer, and breast cancer. Solid tumors may also benefit from CNDAC, decitabine, tezacitabine and/or DMDC.
  • CDA such as gemcitabine, Ara-C, CNDAC,
  • the kit is a ready-to-use kit which, besides the leaflet, comprises seven containers: a container comprising cytidine; a container comprising ammonium; a container comprising sodium and phosphate buffers; a container comprising phenol and nitroprusside; - a container comprising tungstate; a container comprising hypochlorite; and a container comprising sulphuric acid.
  • kit and the protocol may be as follows:
  • Solutions are aliquoted as working solutions (vol : 1 ml, except for solution A : 20 ml and solution D : 15 ml) and stored at -80 0 C.
  • a blood sample is obtained when the patient is not undergoing chemotherapy and stored at 4°C.
  • the blood tube is centrifuged at 2500 rpm, during 20 min and at 4°C, then the serum fraction is isolated.
  • the incubation is stopped by adding 400 ⁇ l_ of solution F into the blank samples.
  • the reaction is stopped by precipitating proteins with 200 ⁇ l solution B + 200 ⁇ l_ solution G. After centrifugation (5000 rpm, room temperature,-5 min) 500 ⁇ l_ of supernatant are recovered.
  • Coupling is achieved by adding 1.5 ml solution D and 2 ml solution E. The mixture is vortexed and incubated during 30 min at 37°C, before being read at 630 nm. The means of the two activities per patient is calculated after subtracting the blank value.
  • the CDA activity is expressed as Activity Units (U) taking into account the level of serum proteins.
  • Toxic-Death Case A 74-year old Caucasian female patient underwent gemcitabine/carboplatin therapy for her metastatic vesical cancer, as following: gemcitabine D1 + D8 (1250 mg/m 2 /day) combined with adapted carboplatin (AUC5) on D2 [8]. Soon after the end of the D8 infusion of gemcitabine (e.g., D 17), this patient showed extremely severe haematological toxicities (G4 neutropenia, G4 thrombopenia, G3 anemia, sepsis, WHO grading).
  • Residual serum CDA activity was assayed as a surrogate marker for the overall functionality of this enzyme.
  • a wash- out period of minimum 15-day e.g., 1500 half-lives of gemcitabine
  • CDA activity was assayed following a simplified spectrophotometric method modified from the literature, based upon the release and detection of ammonium from cytidine [9].
  • Genomic DNA were obtained after standard extraction from whole blood with the QIAamp DNA blood extraction kit (Qiagen, France). Genomic DNA were quantified spectrophometrically at 260nm, and 10 ng were used for each PCR run. The three most relevant polymorphisms, i.e. 79A>C, 208G>A, 435T>C, were checked by high resolution melting (HRM) analysis [10]. Primers were designed in order to yield small amplicons containing putative sequence variation. PCR and post-PCR melting of double-stranded amplicons were carried out on the LightcyclerTM 480 instrument (Roche-Diagnostics, Meylan, France) using the HRM mastermixTM according to the manufacturer procedure.
  • HRM high resolution melting

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Abstract

L'invention porte sur un procédé in vitro pour déterminer le risque de toxicité de l'absorption d'un agent chimiothérapeutique chez un patient atteint d'un cancer, le métabolisme de l'agent chimiothérapeutique mettant en jeu la cytidine déaminase (CDA). Le procédé consiste à déterminer l'activité de CDA dans un échantillon biologique du patient, une altération de l'activité de CDA par rapport à une valeur de commande étant indicative d'un risque de toxicité de l'absorption de l'agent chimiothérapeutique.
PCT/EP2007/058349 2007-08-13 2007-08-13 Procédé d'évaluer du risque de toxicité d'une chimiothérapie WO2009021551A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011061278A1 (fr) 2009-11-20 2011-05-26 Universite De La Mediterranee Procédé permettant d'évaluer la capacité d'un patient à répondre à une chimiothérapie à base d'analogue nucléosidique ou à être traité sans risque par une telle chimiothérapie
WO2011077080A1 (fr) * 2009-12-21 2011-06-30 Guy's And St.Thomas' Nhs Foundation Trust Procédé de prévision de la toxicité de la capécitabine
EP2348131A1 (fr) 2010-01-22 2011-07-27 Institut Curie Niveaux bas de cytidine désaminase en tant que marqueur de la prédisposition génétique de développer un cancer
US8268800B2 (en) 2007-10-16 2012-09-18 Eisai Inc. Certain compounds, compositions and methods
US8324180B2 (en) 2009-04-06 2012-12-04 Eisai Inc. Compositions and methods for treating cancer
US8329665B2 (en) 2009-04-06 2012-12-11 Eisai Inc. Compositions and methods for treating cancer
US8329666B2 (en) 2009-04-06 2012-12-11 Eisai Inc. Compositions and methods for treating cancer
US8609631B2 (en) 2009-04-06 2013-12-17 Eisai Inc. Compositions and methods for treating cancer
WO2016029889A1 (fr) * 2014-08-26 2016-03-03 Univerzita Palackeho V Olomouci Procédé de détermination de l'activité d'enzymes de conversion de dérivés de cytosine en dérivés d'uracile dans des cellules, des tissus et des organismes
WO2017158050A1 (fr) * 2016-03-16 2017-09-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de la cytidine désaminase pour le traitement du cancer du pancréas

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8951987B2 (en) 2007-10-16 2015-02-10 Otsuka Pharmaceuticals Co., Ltd. Certain compounds, compositions and methods
US8618075B2 (en) 2007-10-16 2013-12-31 Eisai Inc. Certain compounds, compositions and methods
US9567363B2 (en) 2007-10-16 2017-02-14 Otsuka Pharmaceutical Co., Ltd. Certain compounds, compositions and methods
US8268800B2 (en) 2007-10-16 2012-09-18 Eisai Inc. Certain compounds, compositions and methods
US9040501B2 (en) 2009-04-06 2015-05-26 Otsuka Pharmaceutical Co., Ltd. Compositions and methods for treating cancer
US8324180B2 (en) 2009-04-06 2012-12-04 Eisai Inc. Compositions and methods for treating cancer
US8609631B2 (en) 2009-04-06 2013-12-17 Eisai Inc. Compositions and methods for treating cancer
US8329665B2 (en) 2009-04-06 2012-12-11 Eisai Inc. Compositions and methods for treating cancer
US8329666B2 (en) 2009-04-06 2012-12-11 Eisai Inc. Compositions and methods for treating cancer
WO2011061278A1 (fr) 2009-11-20 2011-05-26 Universite De La Mediterranee Procédé permettant d'évaluer la capacité d'un patient à répondre à une chimiothérapie à base d'analogue nucléosidique ou à être traité sans risque par une telle chimiothérapie
GB2489180A (en) * 2009-12-21 2012-09-19 Guy S And St Thomas S Nhs Foundation Trust Method of predicting capecitabine toxicity
GB2489180B (en) * 2009-12-21 2014-03-12 Guy S And St Thomas S Nhs Foundation Trust Predicting capecitabine toxicity
WO2011077080A1 (fr) * 2009-12-21 2011-06-30 Guy's And St.Thomas' Nhs Foundation Trust Procédé de prévision de la toxicité de la capécitabine
EP2348131A1 (fr) 2010-01-22 2011-07-27 Institut Curie Niveaux bas de cytidine désaminase en tant que marqueur de la prédisposition génétique de développer un cancer
WO2011089197A1 (fr) 2010-01-22 2011-07-28 Institut Curie Faibles taux de cytidine désaminase comme marqueur pour une prédisposition à développer un cancer
WO2016029889A1 (fr) * 2014-08-26 2016-03-03 Univerzita Palackeho V Olomouci Procédé de détermination de l'activité d'enzymes de conversion de dérivés de cytosine en dérivés d'uracile dans des cellules, des tissus et des organismes
WO2017158050A1 (fr) * 2016-03-16 2017-09-21 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de la cytidine désaminase pour le traitement du cancer du pancréas

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