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WO2003050300A2 - Diagnostic et traitement du cancer - Google Patents

Diagnostic et traitement du cancer Download PDF

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Publication number
WO2003050300A2
WO2003050300A2 PCT/GB2002/005516 GB0205516W WO03050300A2 WO 2003050300 A2 WO2003050300 A2 WO 2003050300A2 GB 0205516 W GB0205516 W GB 0205516W WO 03050300 A2 WO03050300 A2 WO 03050300A2
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WO
WIPO (PCT)
Prior art keywords
clic3
cancer
expression
activity
subject
Prior art date
Application number
PCT/GB2002/005516
Other languages
English (en)
Other versions
WO2003050300A3 (fr
Inventor
Ian Hampson
Lynn Hampson
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The Victoria University Of Manchester
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
Priority claimed from GB0129451A external-priority patent/GB0129451D0/en
Priority claimed from GB0129452A external-priority patent/GB0129452D0/en
Application filed by The Victoria University Of Manchester filed Critical The Victoria University Of Manchester
Priority to AU2002358905A priority Critical patent/AU2002358905A1/en
Publication of WO2003050300A2 publication Critical patent/WO2003050300A2/fr
Publication of WO2003050300A3 publication Critical patent/WO2003050300A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • 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
    • C12Q1/70—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving virus or bacteriophage
    • C12Q1/701—Specific hybridization probes
    • C12Q1/708—Specific hybridization probes for papilloma
    • 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
    • C12Q2600/16—Primer sets for multiplex assays

Definitions

  • the present invention relates to cancer and more particularly to a method of diagnosing whether or not a subject has or is at risk of developing cancer; treatment (including prophylactic treatment) of cancer; and also to methods for identifying agents that may be used to treat cancer or agents that cause cancer.
  • an in vitro method for diagnosing whether or not a subject has, or is likely to develop cancer comprising:
  • the invention has been based on the inventors experiments (see the Examples below) that have established that intracellular chloride channel 3 (Clic3) levels and/or activity are reduced in malignancy. They therefore realised that measurement of Clic3 levels according to the first aspect of the invention may be used as a diagnostic tool for detecting malignant disease as defined herein. Accordingly, measurement of reduced Clic3 activity or reduced Clic3 expression (relative to a non-cancerous sample) is a good indicator that the test subject is suffering from or will develop a cancer.
  • Clic3 intracellular chloride channel 3
  • Clic3 is believed to interact with the cell cycle mitogen activated kinase ERK7 and is known to the art (Qian et al. (1999) J Biol Chem 274 pi 621 -1627). It has the DNA sequence illustrated in Figure 1 (Accession No. XM 005434) and SEQ ID Nol. The start and stop codons are underlined in Figure 1.
  • the subject is preferably a human patient who needs to be assessed for the existence or the risk of developing cancer. It will however be appreciated that the method of the invention will have veterinary applications.
  • the method may be used in the diagnosis of a wide range of cancers such as prostate cancer, colon cancer, ovarian carcinoma, breast carcinoma, thyroid carcinoma, uterine carcinoma, skin cancers (e.g. melanoma), and particularly lung carcinoma.
  • cancers such as prostate cancer, colon cancer, ovarian carcinoma, breast carcinoma, thyroid carcinoma, uterine carcinoma, skin cancers (e.g. melanoma), and particularly lung carcinoma.
  • the invention is also applicable, but by no means exclusively, to cancers caused by oncogenic viruses, e.g. transforming human papilloma viruses (HPNs)
  • HPNs transforming human papilloma viruses
  • the sample taken may, for instance, be a tissue biopsy, blood sample, sputum sample or swab. It will be appreciated that the choice of sample will be dictated by a clinician's suspicions. For instance, lung biopsy samples or sputum samples should be taken if a clinician suspects lung cancer. Skin samples may be taken from subjects suspected of developing melanoma etc. Alternatively serum has been shown to contain tumour derived R ⁇ A and D ⁇ A well before the developing tumour is clinically manifest. Therefore the method of the first aspect of the invention may usefully be carried out on blood or serum samples for testing for a variety of cancers.
  • Samples may be tested from a subject believed to be suffering from cancer, or alternatively samples may be tested from a patient believed to be at risk of developing cancer. We believe the method is suitable for identifying a risk as changes in Clic3 activity and expression may precede other symptoms of carcinogenesis.
  • the level of activity or expression levels of Clic3 in the sample may be compared with the levels of activity or expression levels of Clic3 from a variety of non-cancerous samples.
  • the non-cancerous sample may be taken from "normal" tissue in a subject being tested and a preferred embodiment of the invention involves taking two samples from a subject: one from suspect tissue/cells and the other from non-cancerous tissue/cells. Alternatively a single sample of suspect cells may be taken and a clinician may then compare the activity or expression levels of Clic3 against known standards for normal tissue expression or activity.
  • Diagnosis according to the invention may be effected in order to establish whether or not a patient is suffering from cancer.
  • diagnosis may be effected in order to assess the suitability of a specified therapeutic regime for the treatment of a patient's disease.
  • the activity or expression of Clic3 may be measured using a number of conventional techniques. For instance, labelled antibodies against Clic3 may be used in an immunoassay to evaluate levels of Clic3 expression in the cells or subject being tested. Alternatively a functional activity measuring Clic3 chloride transport may be employed.
  • cDNA may be generated from mRNA extracted from the tested cells or subject and Clic3 primers (e.g. those disclosed in the Example) used in a Polymerase Chain Reaction to amplify cDNA coding for Clic3.
  • Clic3 primers e.g. those disclosed in the Example
  • a most preferred method for detecting Clic3 expression according to the invention is disclosed in Example 2 and the associated figures.
  • kits comprising PCR primers for amplifying cDNA encoding Clic3.
  • Suitable PCR primers for the kit include DNA molecules of SEQ ID No. 2 and SEQ ID No. 3 in Example 2.
  • the kit may further comprise:
  • Buffers provided with the Kit may be in liquid form and preferably provided as pre-measured aliquots.
  • the buffers may be in concentrated (or even be in powder form) for diluting.
  • the Kit may further comprise suitable reaction vessels, centrifuge tubes etc.
  • a third aspect of the invention there is provided the use of an agent that incease cellular levels of the Clic3 protein or increase Clic3 activity in the manufacture of a medicament for the treatment of cancer.
  • a method of treating (including prophylactic treatment) cancer comprising administering to a subject in need of such treatment a therapeutically effective amount of an agent that increases cellular levels of the Clic3 protein or increases Clic3 activity.
  • the uses according to the third and fourth aspects of the invention are based on the inventors experiments (see the Examples below) that have established that intracellular chloride channel 3 (Clic3) levels and/or activity are reduced in malignancy. They therefore realised that agents used according to the third or fourth aspects of the invention may be used for the treatment of malignant disease.
  • the invention may be applied to a wide range of cancers such as colon cancer, prostate cancer, ovarian carcinoma, breast carcinoma, thyroid carcinoma, uterine carcinoma and particularly lung carcinoma.
  • the invention is also applicable, but by no means exclusively, to cancers caused by oncogenic viruses, e.g. transforming human papilloma viruses (HPNs).
  • HPNs transforming human papilloma viruses
  • the agents may be used to treat cancer as a monotherapy (i.e. use of the agent alone or in combination with other compounds or treatments used in cancer therapy (e.g. chemotherapeutic agents, radiotherapy).
  • the medicaments of the third or fourth aspects of the invention may take a number of different forms depending, in particular on the manner in which the medicament is to be used.
  • the medicament may be in the form of a powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micelle, liposome or any other suitable form that may be administered to a person or animal.
  • the vehicle of the medicament of the invention should be one which is well tolerated by the subject to whom it is given and enables delivery of the agents to the effected site.
  • Therapy with the agents may be effected in a number of ways.
  • systemic administration may be required in which case the agent may be contained within a medicament that may, for example, be ingested orally in the form of a tablet, capsule or liquid.
  • the medicament may be administered by injection into the blood stream. Injections may be intravenous (bolus or infusion) or subcutaneous (bolus or infusion).
  • the agents may also be administered by inhalation (e.g. intranasally).
  • the agents may be administered transdermally by way of patches.
  • the agent may also be incorporated within a slow or delayed release device.
  • a slow or delayed release device Such devices may, for example, be inserted under the skin and the agent may be released over weeks or even months.
  • the devices may be particularly advantageous when an agent is used which would normally require frequent administration (e.g. at least daily ingestion of a tablet or daily injection).
  • the amount of an agent required is determined by biological activity and bioavailability which in turn depends on the mode of administration, the physicochemical properties of the agent employed and whether the agent is being used as a monotherapy or in a combined therapy.
  • the frequency of administration will also be influenced by the abovementioned factors and particularly the half-life of the agent within the subject being treated.
  • a daily dose of between O.Ol ⁇ g/kg of body weight and l.Og/kg of body weight of an agent according to the first or second aspects of the invention may be used for the treatment of cancer depending upon which specific agent is used. More preferably the daily dose is between O.Olmg/kg of body weight and lOOmg/kg of body weight.
  • the required dose will be influenced by the route of administration. For instance when an agent is given intravenously the preferred dose may be lower than a suitable dose chosen for oral administration.
  • Daily doses may be given as a single administration (e.g. a daily tablet for oral consumption or as a single daily injection).
  • the agent used may require administration twice or more times during a day.
  • a patient receiving treatment may take a first dose upon waking and then a second dose in the evening (if on a two dose regime) or at 3 or 4 hourly intervals thereafter.
  • a slow release device may be used to provide optimal doses to a patient without the need to administer repeated doses.
  • a preferred means of using protein or peptide agents according to the invention is to deliver the protein or peptide to the tumour site by means of gene therapy.
  • gene therapy may be used to modulate the expression of Clic3 or increase expression of enzyme(s) responsible for the metabolism of Clic3. Therefore according to a fifth aspect of the present invention there is provided a delivery system for use in a gene therapy technique, said delivery system comprising a DNA molecule encoding for a protein which directly or indirectly increases Clic3 expression or activity, said DNA molecule being capable of being transcribed to allow the expression of said protein and thereby treat cancer.
  • the delivery systems according to the fifth aspect of the invention are highly suitable for achieving sustained levels of a protein that directly or indirectly increase Clic3 expression and activity over a longer period of time than is possible for most conventional therapeutic regimes.
  • the delivery system may be used to induce continuous protein expression from cells of the tumour that have been transfected with the DNA molecule. Therefore, even if the protein has a very short half-life as an agent in vivo, therapeutically effective amounts of the protein may be continuously expressed from the treated tissue.
  • the delivery system of the invention may be used to provide the DNA molecule (and thereby the protein which is an active therapeutic agent) without the need to use conventional pharmaceutical vehicles such as those required in tablets, capsules or liquids.
  • the delivery system of the present invention is such that the DNA molecule is capable of being expressed (when the delivery system is administered to a patient) to produce a protein that directly or indirectly has activity for increasing Clic3 expression or activity.
  • directly we mean that the product of gene expression er se has the required activity.
  • indirectly we mean that the product of gene expression undergoes or mediates (e.g. as an enzyme) at least one further reaction to provide an agent effective for increasing Clic3 expression or activity and thereby treating cancer.
  • the DNA molecule may encode for any of the peptide agents as defined above.
  • the DNA molecule may particularly encode for Clic3 per se (see Figure 1) and functional analogues or fragments thereof.
  • the DNA molecule may be contained within a suitable vector to form a recombinant vector.
  • the vector may for example be a plasmid, cosmid or phage.
  • Such recombinant vectors are highly useful in the delivery systems of the invention for transforming cells with the DNA molecule.
  • Recombinant vectors may also include other functional elements.
  • recombinant vectors can be designed such that the vector will autonomously replicate in the cell. In this case, elements which induce DNA replication may be required in the recombinant vector.
  • the recombinant vector may be designed such that the vector and recombinant DNA molecule integrates into the genome of a cell. In this case DNA sequences which favour targeted integration (e.g. by homologous recombination) are desirable.
  • Recombinant vectors may also have DNA coding for genes that may be used as selectable markers in the cloning process.
  • the recombinant vector may also further comprise a promoter or regulator to control expression of the gene as required.
  • the DNA molecule may (but not necessarily) be one that becomes incorporated in the DNA of cells of the subject being treated. Undifferentiated cells may be stably transformed leading to the production of genetically modified daughter cells (in which case regulation of expression in the subject may be required e.g. with specific transcription factors or gene activators). Alternatively, the delivery system may be designed to favour unstable or transient transformation of differentiated cells in the subject being treated. When this is the case, regulation of expression may be less important because expression of the DNA molecule will stop when the transformed cells die or stop expressing the protein (ideally when the cancer has been treated or prevented).
  • the delivery system may provide the DNA molecule to the subject without it being incorporated in a vector.
  • the DNA molecule may be incorporated within a liposome or virus particle.
  • the "naked" DNA molecule may be inserted into a subject's cells by a suitable means e.g. direct endocytotic uptake.
  • the DNA molecule may be transferred to the cells of a subject to be treated by transfection, infection, microinjection, cell fusion, protoplast fusion or ballistic bombardment.
  • transfer may be by ballistic transfection with coated gold particles, liposomes containing the DNA molecule, viral vectors (e.g. adenovirus) and means of providing direct DNA uptake (e.g. endocytosis) by application of the DNA molecule directly to the cancer or prospective site of cancer, either topically or by injection.
  • the treatment according to the third, fourth of fifth aspects of the invention may be for the purposes of treating an existing cancer or may be a prophylactic treatment administered to a person believed to be at risk of developing such a cancer.
  • a method of screening a compound to test whether or not the compound has efficacy for treating cancer comprising:
  • a method of screening a compound, to test whether or not the compound causes cancer comprising:
  • Clic3 expression is reduced in cancerous tissues compared to normal tissues. Accordingly any compound, identified according to the sixth aspect of the invention, that increases the expression or activity of Clic3 is a good candidate as an agent for treating cancer. It will be appreciated that the pharmaceutical industry will be able to use the method according to the sixth aspect of the invention in high throughput screens to identify candidate medicaments for use in the treatment of cancer. Therefore according an eighth aspect of the present invention there is provided an anti-cancer agent identified by the method according to the sixth aspect of the invention
  • the method according to the seventh aspect of the invention represents a good test for evaluating whether or not a test compound is carcinogenic. Accordingly any compound, identified according to the seventh aspect of the invention, that reduces the expression or activity of Clic3 is likely to be carcinogenic.
  • the method may be used to screen compounds to assess whether or not they are safe to be used by the public. For instance cosmetics, foodstuffs, candidate therapeutic agents etc may all be tested to investigate whether or not they may cause cancer.
  • the method according to the seventh aspect of the invention may also be used in an environmental setting. For instance, the test may be used to evaluate whether or not effluent from a factory may contain carcinogenic compounds.
  • Clic3 The activity or expression of Clic3 may be measured using a number of conventional techniques. For instance, labelled antibodies against Clic3 may be used in an immunoassay to evaluate levels of Clic3 expression in the cells or subject being tested. Alternatively a functional activity measuring Clic3 chloride transport may be employed. It is preferred that molecular biology techniques are used to detect Clic3 expression according to the sixth or seventh aspects of the invention. For instance, cDNA may be generated from mRNA extracted from the tested cells or subject and Clic3 primers (e.g. those disclosed in the Examples) used in a Polymerase Chain Reaction to amplify cDNA coding for Clic3. A most preferred method for detecting Clic3 expression according to the sixth or seventh aspects of the invention is disclosed in Example 2 and the associated figures.
  • Cells used according to the sixth or seventh aspects of the invention may be from a number of sourses.
  • the cells may be ex vivo samples but are preferably a cell- line that is either capable of expressing Clic3 or has been engineered to do so.
  • the cell-line is preferably eukaryotic and ideally a human cell line.
  • yeast may be used and even prokaryotic models that have been engineered to be capable of expressing Clic3.
  • the cells may be cultured with a test compound for a predetermined length of time and then tested for levels of Clic3 expression or activity.
  • test compound When a subject is used (e.g. an animal model or preferably an animal model engineered to express human Clic3), the test compound should be administered to the subject for a predetermined length of time and then a sample taken from the subject for testing Clic3 expression or activity.
  • the sample may for instance be blood or biopsy tissue.
  • Figure 1 illustrates the cDNA sequence of Clic3 (SEQ ID No.l);
  • Figure 2 is a plate of yeast colonies from a yeast two hybrid experiment
  • Figure 3 illustrates a Standard RT-PCR analysis of Clic3 expression showing down regulation of Clic3 in primary lung cancer
  • Figure 4 illustrates a comparative multiplex RT-PCR analysis of Clic3 expression in primary lung cancer and shows Clic3 is downregulated in 8/9 primary tumours whereas HEL is a control gene consistently expressed in normal lung and carcinoma tissue;
  • Figure 5 illustrates a comparative multiplex RT-PCR analysis: Clic3 vs control in the specified cell lines.
  • the inventors used a yeast two hybrid technique to identify Clic3 as a protein that is involved in carcinogenesis.
  • the technique is based upon the inventors hypothesis that a two hybrid technique can be used in which cDNA library expression products may be screened for interaction with specific Human Papilloma Virus (HPV) proteins. According to the inventors hypothesis any binding between the cDNA expression product and the HPV proteins suggests the expression product is involved in carcinogenesis.
  • HPV Human Papilloma Virus
  • Clic3 as a modulator of carcinogenesis by screening a human placental cDNA library and found that a new protein (subsequently identified as Clic3) was a target of the HPV 16 E6 protein.
  • cDNA samples taken from normal individuals and cancer patients were subjected to PCR with Clic3 primers to evaluate if Clic3 expression was correlated with cancer.
  • Clic3 primers were designed that spanned the coding sequence for Clic3 and are shown below (as well as being in italics in Figure 1):
  • Figure 3 shows a standard PCR whereby an equal aliquot of test cDNA was analysed for the expression of the HEL gene, which is known to be equally expressed in normal and lung carcinomas. Comparison of this signal to that obtained for Clic3 indicates that Clic3 is down regulated in the majority of the carcinomas.
  • tumours can present problems when comparing the expression level of any particular gene.
  • the cell type that produces the tumour In a given tissue it is common for the cell type that produces the tumour to be present as a minor component of the whole organ. Therefore since the tumour is mainly derived from this minor component, any expression differences may simply reflect the differences in cell types that are present between normal and tumour tissues.
  • homogeneous cell populations are preferred.
  • other assay methods see below are able to obviate the difficulties associated with heterogeneous cell samples.
  • Lung tissue is unusual in that it has a very high proportion of epithelial cells (approximately 50% of the normal lung) which are the main target for malignant conversion. Lung carcinomas are made up of approximately 80% epithelioid cells thus it is unlikely that differences in gene expression will reflect differences in the epithelial content between normal and tumour tissues.
  • Lung carcinomas are made up of approximately 80% epithelioid cells thus it is unlikely that differences in gene expression will reflect differences in the epithelial content between normal and tumour tissues.
  • tracks 18-30 shows that Clic is extensively down- regulated in 11 out of 13 lung carcinoma cell lines as well as in solid tumour tissue (tracks 34 & 35) whereas the signal from normal breast epithelium is much stronger (track 4). Furthermore 5 out of 10 breast carcinoma cell lines also show extensive down-regulation of Clic3 (tracks 10,11,13, 16 & 17) expression as do 2 out of 3 ovarian carcinoma cell lines (tracks 31 & 32). All these data indicate that the expression of Clic3 is being shut down in the majority of lung and in other cancers. Our data therefore indicate that modulation of Clic3 activity is an integral part of the development of many human cancers.

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Abstract

L'invention concerne une méthode de diagnostic pour savoir si un sujet présente un risque de développer un cancer ou non ou est à risque, cette méthode comprenant la mesure des niveaux d'activité ou d'expression de Clic3. L'invention concerne également le traitement (notamment le traitement prophylactique) du cancer au moyen de modulateurs de Clic3 ainsi que des procédés d'identification d'agents qui peuvent être utilisés pour traiter le cancer ou des agents provoquant le cancer.
PCT/GB2002/005516 2001-12-08 2002-12-06 Diagnostic et traitement du cancer WO2003050300A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002358905A AU2002358905A1 (en) 2001-12-08 2002-12-06 Diagnosis and treatment of cancer

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB0129451A GB0129451D0 (en) 2001-12-08 2001-12-08 Treatment of cancer
GB0129452A GB0129452D0 (en) 2001-12-08 2001-12-08 Diagnosis of cancer
GB0129451.1 2001-12-08
GB0129452.9 2001-12-08

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WO2003050300A2 true WO2003050300A2 (fr) 2003-06-19
WO2003050300A3 WO2003050300A3 (fr) 2004-03-04

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5728579A (en) * 1994-08-11 1998-03-17 President And Fellows Of Harvard College DNA encoding Mat-8
US5854411A (en) * 1997-01-09 1998-12-29 Incyte Pharmaceuticals, Inc. Human chloride channel
WO2002083712A2 (fr) * 2001-04-12 2002-10-24 Incyte Genomics, Inc. Transporteurs et canaux ioniques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5728579A (en) * 1994-08-11 1998-03-17 President And Fellows Of Harvard College DNA encoding Mat-8
US5854411A (en) * 1997-01-09 1998-12-29 Incyte Pharmaceuticals, Inc. Human chloride channel
WO2002083712A2 (fr) * 2001-04-12 2002-10-24 Incyte Genomics, Inc. Transporteurs et canaux ioniques

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE EBI [Online] Homo sapiens chloride intracellular channel 3, 7 May 2001 (2001-05-07) STRAUSBERGER ET AL: retrieved from EBI, accession no. BC007012 XP002256913 *
QIAN, ZHIJIAN ET AL: "Molecular cloning and characterization of a mitogen -activated protein kinase-associated intracellular chloride channel" JOURNAL OF BIOLOGICAL CHEMISTRY ( 1999 ), 274(3), 1621-1627 , 1999, XP002256911 cited in the application *
RONNOV-JESSEN, LONE ET AL: "Differential expression of a chloride intracellular channel gene, CLIC4, in transforming growth factor-.beta.1-mediated conversion of fibroblasts to myofibroblasts" AMERICAN JOURNAL OF PATHOLOGY ( 2002 ), 161(2), 471-480 , 2002, XP002256912 *

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AU2002358905A1 (en) 2003-06-23

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