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WO2003067260A1 - Methode pour diagnostiquer un carcinome ovarien kystique - Google Patents

Methode pour diagnostiquer un carcinome ovarien kystique Download PDF

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Publication number
WO2003067260A1
WO2003067260A1 PCT/AT2003/000031 AT0300031W WO03067260A1 WO 2003067260 A1 WO2003067260 A1 WO 2003067260A1 AT 0300031 W AT0300031 W AT 0300031W WO 03067260 A1 WO03067260 A1 WO 03067260A1
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WO
WIPO (PCT)
Prior art keywords
calgranulin
concentration
ovarian cancer
individual
cell culture
Prior art date
Application number
PCT/AT2003/000031
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German (de)
English (en)
Inventor
Karl Illmensee
Herbert Lindner
Bettina Sarg
Helmut Ott
Original Assignee
Tilak-Tiroler Landeskrankenanstalten Gmbh
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 Tilak-Tiroler Landeskrankenanstalten Gmbh filed Critical Tilak-Tiroler Landeskrankenanstalten Gmbh
Priority to AU2003208154A priority Critical patent/AU2003208154A1/en
Publication of WO2003067260A1 publication Critical patent/WO2003067260A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57449—Specifically defined cancers of ovaries
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present application relates to a method for diagnosing cystic ovarian cancer in an individual or a cell culture.
  • Ovarian cancer is a tumor that is increasingly occurring in the white population in Europe. About 15 out of 100,000 women develop ovarian cancer each year, and this disease is the main cause of mortality among all gynecological diseases. The number of cases of ovarian cancer increases with age, with about 3% of women under 30, 25% of women between 40 and 50 and 35% of women over 50 having this type of tumor.
  • ovarian cancer is difficult to predict. Early symptoms that could be used to identify this condition at an early stage are not known. In most cases, the symptoms only appear at a late stage of the disease and are non-specific. There is usually an increase in the abdominal mass due to ascites.
  • the distribution of the tumor is classified according to FIGO (International Federation of Gynecology and Obstetrics) in stages I to IV, whereby stages I to III are divided into subgroups a, b and c.
  • FIGO International Federation of Gynecology and Obstetrics
  • the histological typing of ovarian tumors is carried out according to the HO (World Health Organization).
  • the three main categories are epithelial tumor, genital ridge - stroma and germ cell tumors. In addition to these groups, there are other histologically defined tumors, but these rarely occur in the area of the ovary.
  • the epithelial tumor is the most common of all ovarian tumors (55%). About 30% of all tumors are serous and 15% mucinous, 75% are benign, 15% align and 10% are borderline tumors. Histological and cytological evaluations of the ascites are necessary to classify and analyze the tumor tissue and tumor spread. Based on the cytogenetic results of ovarian tumors, it was found that this frequently occurs in connection with DNA amplification of the chromosomal region 20 ql2-gl3, similar to the already known amplification in breast cancer. In addition, gene amplification of c-erbB-2 and FGF-3 (INT-2) has been associated with oncogenic processes.
  • ovarian tumors can be detected with the help of various tumor markers, such as CA 125, CA 19-9, AFP, neopterin, interleukin-8, interleukin-12 and hCG.
  • tumor markers such as CA 125, CA 19-9, AFP, neopterin, interleukin-8, interleukin-12 and hCG.
  • Soluble cell adhesion molecules such as the sCD44 protein, sE-cadherin and sICAM-1 have been found in both ovarian cancer and patient serum.
  • sCD44 protein sE-cadherin and sICAM-1
  • Recent studies have shown that the absence of c-kit protein in ovarian cancer is associated with a very low survival rate, with c-kit patients showing a higher survival rate in tumor tissue.
  • cytosol values of uPA, PAI-1 and VEGF show a significant correlation with malignant developments and a low survival rate.
  • Increased VEGF and suPAR values were found in the serum of patients with malignant ovarian cancer.
  • further examination of the sera from patients with ovarian cancer for uPA, PAI-1, HER-2 and VEGF did not lead to the detection of a reliable tumor indicator that could be used for early diagnosis of tumor markings.
  • ARP apoptosis-associated proteins
  • cystic ovarian cancer it has now been found for the first time that there is a connection between the concentration of calgranulin A or calgranulin B in an individual and the diagnosis of cystic ovarian cancer: If cystic ovarian cancer is diagnosed, overexpression of calgranulin A and / or Calgranulin B found compared to healthy individuals or individuals with benign ovarian tumors. This is the first time that a marker for cystic ovarian cancer has been made available that can specifically and reproducibly distinguish not only between healthy people and people suffering from cystic ovarian cancer, but also between malignant and benign Ovarian tumors.
  • diagnosis also means the distinction between semimalignant and benign or semimalignant and malignant ovarian tumors: patients with semimalignant ovarian tumors show a higher concentration of calgranulin A and / or calgranulin B than patients with benign ovarian tumors or healthy patients. Similarly, patients with malignant ovarian cancer show a higher concentration of calgranulin A and / or calgranulin B than patients with semi-malignant ovarian cancer. Although semimalignant ovarian cancer is very rare, the diagnosis of such a borderline case is important. With the help of the determination of the Calgranulin A / B concentration the diagnosis is made much easier and a highly specific and quick diagnosis is now possible with the help of this new procedure.
  • Calgranulin A also called MRP8
  • Calgranulin B also called MRP14
  • MRP8 myeloid-related proteins and belong to the SlOO family of calcium binding proteins.
  • Calgranulin A and Calgranulin B are co-expressed and form a cell surface and cytoskeleton-associated heterodimer after calcium mobilization. This heterodimer is expressed in the cytoplasm of granulocytes and a subpopulation of blood monocytes.
  • Endress et al. (Lung-Cancer 1997 Aug .; 18 (l): 35-46) report the role of macrophages in human lung carcinoma, showing that MRP8 and MRP14 positive macrophages were present in fewer cases in lung carcinoma, while in 27 10 positive cells were increasingly present.
  • WO 00/26668 A2 discloses a method for diagnosing cancer, wherein values of S 100-AG, S 100-A7, S 100-A8 and S 100-A9 are measured in a sample of a person's biological fluid and with a Control value to be compared. An increased concentration, at least one of these proteins, indicates cancer, in particular breast, colon or Lung cancer, close.
  • calgranulin A and calgranulin B proteins of the SlOO family of calcium binding proteins relate to the proteins MRP8 (S100-A8) and MRP14 (S100-A9) as described, for example, in Eue et al. (Int-Immunol. 2000 Nov; 12 (11): 1593-604), the content of which is incorporated by reference into the present application.
  • “individual” is understood to mean, in particular, a human being but also a mammal which can develop cystic ovarian cancer.
  • the "cell culture” relates to any in vifcr ⁇ cultivation of cells, in particular ovarian cells, which may have been taken from a healthy individual, for example, and the development or development of a cystic ovarian carcinoma can be examined on the basis of this cell culture.
  • the cell culture can also be a culture of cells that have been removed from a patient with a positive diagnosis for cystic ovarian cancer.
  • the concentration of calgranulin A / B is determined in a sample taken from the individual, the sample preferably being a body or organ fluid or an organ or tissue sample, such as serum, cyst fluid, ovarian tissue but also urine, etc.
  • a sample taken from the individual preferably being a body or organ fluid or an organ or tissue sample, such as serum, cyst fluid, ovarian tissue but also urine, etc.
  • Cell culture becomes the tration determined either in the cell culture directly or in a sample taken from the cell culture, for example supernatant or the cells themselves.
  • the concentration is determined in accordance with a suitable method, the method being selected depending on the type of sample, the laboratory possibilities, the number of samples to be determined, but also on the desired accuracy.
  • the calgranulin A / B concentration can be carried out, for example, electrophoretically, chromatographically, immunologically, colorimetrically or by a combination of these methods. Since a number of anti-calgranulin A / B antibodies are already available, immunological tests are extremely suitable, which can either be carried out directly on the tissue sample or in the liquid, for example with the help of ELISA. Testing.
  • the reference value is the calgranulin A / B content in a corresponding "healthy” or “benign” sample or cell culture, i.e. a sample taken from an individual who is not suffering from cystic ovarian cancer or a cell culture which has no cystic ovarian cancer.
  • the reference value is the calgranulin A / B content e.g. in a corresponding "semimalignant" sample or cell culture or the limit calgranulin A / B content, i.e.
  • the reference value should preferably come from a corresponding sample, i.e. if the concentration in cyst fluid is determined, the reference value should also be from cyst fluid.
  • the determined concentration is above the reference value, this means an overexpression of calgranulin A / B compared to the reference or normal value, whereby this means a disease (malignant or semimalignant) of cystic ovarian cancer.
  • the concentration of calgranulin A or that of calgranulin B or the concentrations of of the proteins are determined, the reference value of course being the corresponding concentration, ie likewise either calgranulin A or calgranulin B or both together.
  • the calgranulin A concentration is particularly suitable for diagnosis.
  • a patient is not examined to determine whether he is generally suffering from cancer, but rather the patient can generally be examined as soon as he experiences pain or other abnormalities in a specific organ or body area feels.
  • the breast is examined, if the patient has difficulty breathing, the doctor would examine the lungs in a first step, and in the present case, for example, the patient would feel pain in the lower abdomen, so the doctor would presumably over in a first step Ultrasound examinations would determine whether cyst-like growths can be seen in the area of the ovaries, fallopian tubes or uterus.
  • the reference value is preferably the concentration of calgranulin A and / or calgranulin B in a sample taken from a healthy individual or in a carcinoma-free cell culture. door. This reference value is particularly useful for distinguishing between (semi) malignant and benign tumors or healthy people.
  • a healthy individual is understood to mean a corresponding individual who is free from cystic ovarian cancer.
  • the individual from whom the reference value is determined should be the same as that in which the calgranulin A / B concentration is determined. That is, if the concentration is determined in one person, the reference value should also be determined in another person in a corresponding sample.
  • Another aspect of the present application relates to a method for determining the positive or negative development of cystic ovarian cancer in an individual or a cell culture, which comprises the steps:
  • a positive development of the cystic ovarian cancer being determined if the determined concentration (s) is above the concentration value of the earlier one taken sample lies.
  • This method allows the development of the disease to be determined, a positive development meaning a spreading or growth of the cystic ovarian cancer, ie a worsening of the disease state, and a negative development a reduction or even disappearance of the cystic ovarian cancer, ie an improvement in the Disease state means.
  • the earlier point in time can be the concentration value a few days, a week, months or even years ago.
  • the concentration value can be that which was determined at the earlier point in time. In order to prevent possible inaccuracy of determination, however, it is also possible to carry out the concentration value simultaneously on both samples, the sample taken at the earlier point in time being preserved in a suitable form, for example in a frozen state.
  • the sample taken from the individual is preferably selected from the group consisting of cyst fluid, cyst tissue, serum and urine.
  • cyst fluid and serum have been found to be suitable for the method according to the invention, and these samples can be taken in a simple manner in the course of routine examinations, which is a very uncomplicated and inexpensive way of detecting or examining cystic ovarian cancer.
  • a particularly advantageous method is that the concentration of calgranulin A and / or calgranulin B is determined immunologically. These immunological determinations are particularly favorable since a number of polyclonal as well as monoclonal antibodies which are specific for calgranulin A and calgranulin B exist. Immunological procedures can be carried out both in liquid and on tissues. Examples of such methods are standard ELISA, sandwich ELISA, immunohistochemical methods, etc., these methods not only making it possible to detect calgranulin A / B, but also an accurate quantification.
  • the concentration of calgranulin A and / or calgranulin B is preferably determined using monoclonal antibodies.
  • Monoclonal antibodies are highly specific and can be produced in a very simple and cost-effective manner using standard methods.
  • monoclonal antibodies specific for calgranulin A / B already exist and are readily available.
  • concentration of calgranulin A and / or calgranulin B is determined by measuring the corresponding mRNA or fragments thereof.
  • the measurement of mRNA molecules can be carried out by any conventional method, in particular by hybridization reactions or PCR, it being sufficient to detect a specific region in the mRNA molecule. This method can also be carried out directly in the sample.
  • Another aspect of the present invention relates to a kit for the detection of cystic ovarian cancer in an individual or a cell culture, the
  • Calgranulin A includes a Calgranulin A and / or Calgranulin B reference agent.
  • the reagent for determining the concentration of calgranulin A / B naturally depends on the respective detection method, although the kit can of course also comprise two or more reagents if these are necessary for the detection method.
  • the reagent can e.g. Antibodies, buffers with detection substances and the like include.
  • further detection means such as fluorescent, radioactive or chromogenic substances or also secondary antibodies, can be provided.
  • the reference agent is, for example, a sample comprising a standardized concentration of calgranulin A / B, for example in a buffer or also in a solution corresponding to the respective body fluid or cell culture sample.
  • the reference means can also consist of a simple comparison value, a comparison table or a comparison curve.
  • the reagent for determining the concentration of calgranulin A and / or calgranulin B antibodies preferably comprises, in particular monoclonal antibodies. It is advantageous here if the antibodies are present in the reagent in a certain concentration, the anti-calgranulin A and anti-calgranulin B antibodies being able to be provided separately from one another but also together in the reagent.
  • the antibodies can be bound to markers, for example to fluorescent, radioactive or chromo- gene groups or secondary antibodies that are specific for the primary antibodies can also be provided in the kit.
  • the antibodies are preferably immobilized on a solid support. This makes it possible for the samples to be applied only to the solid support or to flow over it, with calgranulin A / B being immobilized on the solid support via the antibodies. Then washing steps can be carried out and the detection either directly on the solid support or after elution in the eluate.
  • the carrier can be, for example, a chromatography column, a filter, a microtiter plate, well, etc.
  • the kit comprises a solid support for immobilizing calgranulin A and / or calgranulin B.
  • This solid support can be provided, for example, with the natural binding partners of calgranulin A / B, their analogs, parts of antibodies and the like.
  • the detection can again be carried out either directly on the solid support, for example with the aid of labeled or unlabeled antibodies, or after an elution step in the eluate.
  • one of the carriers defined above can be provided as the carrier.
  • the reference agent particularly preferably comprises a standardized amount of calgranulin A and / or calgranulin B. This provides a kit which ensures parallel determination of the reference value, thereby eliminating possible inaccuracies in the determination method.
  • a further advantageous embodiment consists in the reference means comprising a series of standardized calgranulin A and / or calgranulin B samples. These samples can e.g. represent certain degrees of disease, so that the extent or stage of the disease can be determined with the help of only one determination method.
  • Another aspect of the present application relates to the use of calgranulin A and / or calgranulin B inhibitors for the manufacture of a medicament for the treatment of cystic ovarian cancer. Since the concentration of calgranulin A and / or calgranulin B is directly related to a disease of cystic ovarian cancer, a reduction in the concentration of calgranulin A / B or a complete switch-off of calgranulin A / B can prevent a disease or as Therapy for a patient already suffering from cystic ovarian cancer.
  • calgranulin A and / or calgranulin B inhibitors are understood to mean substances, molecules or proteins which, for example, prevent or reduce the expression of calgranulin A / B at the transcription level or translation level, specifically attack and, if appropriate, destroy proteins already expressed , blocks the activity of expressed calgranulin A / B proteins etc.
  • calgranulin A / B inhibitors mean calgranulin A / B antibodies, in particular monoclonal antibodies and also antibody fragments.
  • non-active calgranulin A / B analogs could also be used, which act competitively with natural calgranulin A / B.
  • calgranulin A / B inhibitors could be those which are used in gene silencing, knockout or antisense processes.
  • either calgranulin A or calgranulin B inhibitors can be used here. But it is also possible to use both in a coordinated relationship to each other in one drug.
  • Another aspect of the present application relates to a method for treating a patient with cystic ovarian cancer, which is characterized in that the patient is administered a sufficient amount of calgranulin A and / or calgranulin B inhibitors.
  • treatment means both the treatment of malignant or semi-malignant carcinomas and the prevention of a worsening of the disease in the case of a benign carcinoma. The prevention of a disease in a healthy patient is also understood.
  • FIGS. 1 to 3 the results of 2D gel electrophoresis examinations of various samples and FIGS. 4 and 5 show the amino acid sequences of MRP8 and MRP14.
  • example 1 the results of 2D gel electrophoresis examinations of various samples and FIGS. 4 and 5 show the amino acid sequences of MRP8 and MRP14.
  • Liquids from malignant, benign, and borderline ovarian tumors were collected during surgery or during routine examination. After centrifugation, these samples were aliquoted and frozen like the pellets. Blood samples from the same patients were also collected on the same day, and the supernatants were also divided into pellets and frozen after centrifugation.
  • a quantitative analysis of the aliquots of the liquid samples was carried out to determine the total amount of protein according to the Lowry method.
  • denaturing agents were added to the aliquots in order to dissociate the proteins and to reduce the disulfide bridge bonds.
  • the proteins were separated by means of IEF (isoelectric focusing) in an electrical field (pH 3-10).
  • IEF isoelectric focusing
  • an electrical field pH 3-10
  • a second separation of the proteins was then carried out in an acrylamide gradient gel (9-16%).
  • the protein spots that position in the second dimension are therefore characterized by two independent parameters, on the one hand by the isoelectric focusing and on the other hand by the molecular weight.
  • the protein spots on the 2D gel are made visible using a modified silver staining method according to Blum. This method allows the identification of more than 100 proteins in the fluid of various ovarian tumors and in the serum of the patients, so that the different protein patterns can be compared.
  • FIGS. 1 to 3 show samples from a patient with mucinous cystic carcinoma grade II / FIGO Ilb
  • FIG. 2a shows a sample from a patient with serous cystic carcinoma.
  • C means cyst fluid
  • S serum.
  • the results show that the protein patterns of the ovarian cancer fluids are significantly different compared to the ovarian cyst fluids. Particularly in the lower molecular range between 10 and 25 kD (see broad arrow in FIGS. 1 to 3), numerous additional protein spots can be seen both in the cyst fluid and in the serum of the patients with ovarian cancer (see FIGS. 1 a to 3 a) compared to patients with benign ovarian cysts (see figures lb to 3b).
  • protein spots 1 were identified as calgranulin A (FIG. 4) and 2 as calgranulin B (FIG. 5), the respective sequence with its amino acids and also as a schematic representation being shown, "M” the mean mass , "S” sequence and "P” position mean.
  • M the mean mass
  • the amount of protein present with 100-300 ng protein per spot, based on the total protein amount of 100 ⁇ g examined in the 2D gel, is also sufficient for immunological tests. The localization of these two proteins in the 2D gel was carried out for the first time.
  • additional proteins in the lower molecular range between 10 and 20 kD were found in the serum samples of the 13 patients with ovarian cancer. These additional proteins in the serum show strong similarities in their electrophoretic positioning to those found in the cyst fluids of the corresponding ovarian cancer patients. These additional proteins are not detectably present in the serum of patients with benign ovarian cysts.

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Abstract

L'invention concerne une méthode pour diagnostiquer un carcinome ovarien kystique chez une femme ou dans une culture cellulaire, cette méthode consistant à déterminer la concentration de calgranuline A et/ou de calgranuline B dans un échantillon prélevé sur la personne ou dans la culture cellulaire, et à comparer les concentrations ainsi déterminées avec au moins une valeur de référence, un carcinome ovarien kystique étant diagnostiqué lorsque la(les) concentration(s) obtenue(s) dépasse(nt) la valeur de référence. La présente invention porte également sur un kit pour détecter un carcinome ovarien kystique chez une patiente ou dans une culture cellulaire.
PCT/AT2003/000031 2002-02-07 2003-01-31 Methode pour diagnostiquer un carcinome ovarien kystique WO2003067260A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003208154A AU2003208154A1 (en) 2002-02-07 2003-01-31 Method for the diagnosis of a cystic ovarian carcinoma

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Application Number Priority Date Filing Date Title
ATA200/2002 2002-02-07
AT0020002A AT412026B (de) 2002-02-07 2002-02-07 Verfahren zur diagnose eines zystischen ovarialkarzinoms

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NO20110895A1 (no) * 2011-06-21 2012-12-24 Magne Fagerhol Kompetitive S100A9 immunoanalyser

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000026668A2 (fr) * 1998-11-05 2000-05-11 The Regents Of The University Of Michigan Proteines s100 et auto-anticorps comme marqueurs seriques pour le cancer
WO2001036644A2 (fr) * 1999-11-18 2001-05-25 Curagen Corporation Polypeptide du type cytokine regule par la proteine wnt et acides nucleiques codant ce polypeptide
WO2002021133A2 (fr) * 2000-09-07 2002-03-14 The Brigham And Women's Hospital, Inc. Procedes de detection du cancer fondes sur la prostasine
WO2002077176A2 (fr) * 2001-03-22 2002-10-03 The Government Of The United States Of America As Represented By The Secretary, Department Of Health And Human Services Proteines presentant une expression aberrante dans des tumeurs microdissequees capturees au laser

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000026668A2 (fr) * 1998-11-05 2000-05-11 The Regents Of The University Of Michigan Proteines s100 et auto-anticorps comme marqueurs seriques pour le cancer
WO2001036644A2 (fr) * 1999-11-18 2001-05-25 Curagen Corporation Polypeptide du type cytokine regule par la proteine wnt et acides nucleiques codant ce polypeptide
WO2002021133A2 (fr) * 2000-09-07 2002-03-14 The Brigham And Women's Hospital, Inc. Procedes de detection du cancer fondes sur la prostasine
WO2002077176A2 (fr) * 2001-03-22 2002-10-03 The Government Of The United States Of America As Represented By The Secretary, Department Of Health And Human Services Proteines presentant une expression aberrante dans des tumeurs microdissequees capturees au laser

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SATO N ET AL: "Cellular characterization of the 91kDa-ectopic ascitic antigen sharing antigenicity with MRP8 in the human placenta as revealed by immunoelectron microscopical colloidal-gold techniques.", OKAJIMAS FOLIA ANATOMICA JAPONICA. JAPAN MAR 1998, vol. 74, no. 6, March 1998 (1998-03-01), pages 217 - 229, XP008018626, ISSN: 0030-154X *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NO20110895A1 (no) * 2011-06-21 2012-12-24 Magne Fagerhol Kompetitive S100A9 immunoanalyser
WO2012175616A1 (fr) * 2011-06-21 2012-12-27 Calpro As Immunodosages compétitifs de s100a9

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