WO2004005540A2 - Uses of ngal-binding substances in the diagnosis and treatment of cancer diseases - Google Patents

Abstract

The invention relates to the uses of Ngal in the diagnosis and treatment of cancer and in the screening of substances for the purposes thereof.

Description

 Uses of Ngal-binding substances for the diagnosis and treatment of cancer.

Field of the Invention

The invention relates to new uses of Ngal or sequences derived therefrom for screening for substances which bind to it, and to the use of substances which bind to Ngal for the diagnosis and / or treatment of tumor diseases.

Background of the Invention and Prior Art

Ngal, also called Lipocalin-2 (LCN2), is a protein that is associated with neutrophil gelatinase in the granulocytes (L. Kjeldsen et al., J Biol Chem, 268: 10432-10432 (1993) and has a molecular weight of 25 kD It is assumed that Ngal has a modulating effect on inflammatory reactions and binds to small lipophilic molecules and formyl peptides (frαlp), which are derived from bacteria, although the latter could not be confirmed experimentally by another group (DH Goetz et al., Biochemistry, 39: 1935-1945 (2000)).

Ngal was identified by screening a human genome library with Ngal cDNA as a gene with 7 exons (JB Cowland et al., Genoics 45: 17-23 (1997)). The primary Tran ^¬ script has a length of 3696 nucleotides and the processed transcript is 809 nucleotides long. In the literature L. Kjeldsen et al. , (2000) is expression von Ngal has been described in various human normal tissues. Ngal is located on chromosome 9q34 (P. Chan et al., Genomics 23: 145-150 (1994)). Cloning and expression of human Ngal cDNA, which originates from bone marrow and ovary cell lines, is described in the reference S. Bartsch et al. , FEBS Lett 9: 255-259 (1995).

High levels of Ngal were found in adenocarcinomas of the lungs, colon and pancreas. In contrast, Ngal levels in renal cell carcino a of different subtypes and prostate tumors are low. Lymphoma and thymic tumors were Ngal negative in immunohistochemical experiments (A. Friedl et al., The Histoche ical Journal 31: 433-441 (1999). According to references US-5, 627, 034, US-5,773,290 and US-5, The proliferation of breast cancer cells is correlated with Ngal overexpression in 846, 739 and US-A-726725 A connection with ovarian tumor is disclosed in the literature reference O-99/53040.

Findings from paired tumor / normal tissues are not known for other types of cancer.

Cancer, especially ovarian, colon, lung and uterine cancer, is a disease of increasing incidence with increasing age. So far, this tumor disease has been diagnosed essentially pathologically and mostly treated by removal. Removal of organs has various adverse effects on a patient. Improved diagnosis and treatment of this type of cancer, especially without the need to remove the organ, is therefore highly desirable. Technical problem of the invention

The invention is based on the technical problem of specifying pharmaceutical compositions for the diagnosis and / or treatment of cancer and means for identifying them.

Fundamentals of the invention and preferred exemplary embodiments.

The invention teaches the use of a nucleic acid coding for Ngal and / or a Ngal peptide or protein for the detection of cancer, in particular of ovarian, colon, lung and / or uterine cancer, or for the detection of a risk of the disease of cancer. in particular of ovarian, colon, lung and / or uterine cancer, a tissue sample (of the tissue in question) being examined for overtranscription of Ngal RNA or for overexpression of a Ngal protein. A coding on for Ngal nucleic acid or binding of NGAL protein or peptide detector substance, preferably containing a reporter group can be used, in which binding ^• said nucleic acid and / or said protein or peptide to the detector substance is detected semi-quantitatively or quantitatively.

The invention further teaches the use of a Ngal RNA or a Ngal protein or peptide for screening for substances binding to it, in particular prospective active substances for inhibiting said RNA or said protein or peptide or prospective detector substances, whereby a prospective substance or a mixture of such prospective substances is contacted with said RNA or said protein or peptide, whereby binding events are determined with a binding assay, and wherein a binding prospective substance, if necessary after deconvolution, as for detection and / or treatment of cancer, in particular of ovarian, colon, lung and / or uterine cancer, is appropriately selected.

Finally, the invention teaches the use of a substance inhibiting or binding to Ngal for the manufacture of a pharmaceutical composition for the treatment of cancer, in particular ovarian, colon, lung and / or uterine cancer. The substance can be an antibody which, for example, by immunizing a non-human mammal with a Ngal peptide or protein, or with Ngal cDNA, or with cells transiently or stably transfected with Ngal cDNA (eg tumor cell lines, NIH3T3, CHO, COS), or with tumor cells expressing endogenous Ngal or with Ngal produced in insect cells, or a phage display is antibody.

However, the substance can also be a facial expression compound of an antibody against an Ngal peptide or protein. Finally, the substance can be an aptamer, an antisense RNA, an inhibitory RNAi, or a ribozyme. The substance can additionally carry a cytotoxic and / or immunostimulating component. The pharmaceutical composition can be prepared for systemic or local application in tissue containing tumor cells. The invention can be used in the context of a method for diagnosing cancer, in particular ovarian, colon, lung and / or uterine cancer, an embodiment of a detector substance with a reporter group being applied to the tissue to be examined, the tissue to be examined Tissue is then subjected to a detection method stage which is sensitive to the reporter group, and in the case of detection of a defined minimum value of the reporter group in the tissue the tissue is qualified as containing tumor cells, and a method for the treatment of cancer, in particular of ovarian, Colon, lung and / or uterine cancer, a pharmaceutical composition according to the invention being administered to a patient in a physiologically effective dose.

The invention is based on the knowledge that Ngal is overexpressed or is differentially expressed in tumors, ie in said tumor tissues the expression is higher compared to (paired) normal cells of the same tissue, and the technical teaching that can be derived therefrom that Ngal can be used as a target molecule in the diagnosis and therapy of this disease. Ngal can therefore serve as a marker for the identification of tumor cells in said tumor tissues. On the other hand, the inhibition of Ngal, especially with local application, offers the possibility to intervene in the tumor-specific Ngal associations with other processes in the tumor cells and thus ultimately to disrupt the metabolism that is specific to the tumor cells and to die or at least die contribute to inhibiting the growth of tumor cells. Within the scope of the invention, it may be advisable to take a sample from a tissue which is identified as tumor tissue by other methods before treatment with a pharmaceutical composition according to the invention and to examine the tissue sample for expression or overexpression of Ngal. Alternatively, it can be tested for Ngal dependence with a detector substance according to the invention for diagnosis in vivo. If expression or overexpression of Ngal with respect to normal tissue of the same type is found, the use of the pharmaceutical composition according to the invention is indicated.

If the tumor is a type in which tumor cells express Ngal, but normal cells of the same tissue type are not, it is particularly preferred if the substance binding to Ngal additionally carries a cytotoxic and / or immunostimulating component. This ultimately leads to the fact that almost exclusively tumor cells are killed, either by the cytotoxicity or by attack by the stimulated immune system, while normal cells are practically completely preserved in the tissue. In this embodiment, the binding substance itself does not have to have an inhibitory effect on Ngal-, since the binding substance then only has to function as a marker which carries the components to target tumor cells. If a cytotoxic and / or immunostimulating component is used, it will be particularly recommended if the pharmaceutical composition is prepared for local application in tissue containing tumor cells, for example for injection. Of independent importance in the context of the invention is the use of a Ngal protein in a screening process for the determination of the secretion of Ngal-modulating substances. This can be done, for example, in such a way that Ngal-expressing cells, in particular Ngal-expressing tumor cells of the tumor types mentioned, are cultivated in a medium, with incubation before or during the cultivation with a prospective secretion-inhibiting substance or with a mixture of such substances the medium is analyzed for Ngal after a defined cultivation period, optionally after the medium has been separated from the cells, and the substance, if appropriate after deconvolution, is selected if the amount of Ngal detected in the medium falls below a defined limit value. In this embodiment, the actual secretion path is irrelevant, since only the secretion as such is the selection criterion. The defined limit can be determined by culturing under the same conditions, but without incubation with a prospective substance that inhibits secretion. A secretion rate which is at least 10%, preferably at least 50%, most preferably at least 90%, below the reference secretion rate can be used as the selection criterion.

Of further independent importance is the alternative use of a Ngal protein in a screening method for finding a Ngal-inhibiting but not its secretion-inhibiting substance, wherein Ngal-expressing cells are cultivated in a medium, before or during the cultivation with a substance selected according to claim 3 or with a mixture such substances is incubated, the medium being analyzed for Ngal after a defined cultivation period, optionally after separation of the medium from the cells, and the substance being selected, if appropriate after deconvolution, if the amount of Ngal detected in the medium is a defined one Limit exceeded. The above statements apply analogously to further training.

This embodiment of the invention is based on the finding that secreted Ngal induces apoptosis in at least some immune cells which play a role in tumor defense. In this respect, Ngal has a paracrine effect. However, secreted Ngal also has an autocrine effect on the proliferation of tumor cells, ie proliferation is induced by secreted Ngal. The secretion of Ngal consequently has an undesirable synergistic effect, namely on the one hand promoting proliferation in the case of tumor cells and on the other hand inducing apoptosis in immune cells which attack tumor cells. Basically, two therapeutic approaches follow from this, namely: i) inhibition of Ngal in the tumor cells themselves, which ultimately also prevents secretion or only inactive Ngal is secreted, and / or ii) inhibition of secreted Ngal, ie outside the tumor cells, which on the one hand results in a Induction of the proliferation of the tumor cells does not occur and, on the other hand, the immune cells attacking the tumor cells are protected against Ngal-induced apoptosis. This results in potential active substances with the following basic properties: i) inhibition of Ngal in the tumor cell; for this purpose, the active ingredient must be membrane permeant, ii) inhibit the Secre ^¬ tion of Ngal; such an active ingredient does not ^necessarily (but can also) reach into the intracellular Ngal Formation, but inhibits the membrane passage formed Ngalε, iii) inhibition of predominantly or exclusively extracellular Ngal; such an active ingredient is not or only poorly permeable to membranes (eg antibodies). Ultimately, in addition to inhibiting the pro-proliferative effect of Ngal on tumor cells, the natural immune response to the tumor is (re-) activated.

It has also been found within the scope of the invention that tumor cells (e.g. human ovarian tumor samples) almost exclusively secrete Ngal in monomeric form, while, for example, granulocytes and transfected insect cells secrete both the monomer and a dimer. On the one hand, this can be used diagnostically for the detection of tumor cells, namely by detecting the secretion predominantly or exclusively as a monomer. Furthermore, therapeutic use can take place in that, for example, a di erization, as a homo- or as a heterodimer, is induced, the dimer thus induced being biologically inactive or inactivated.

Definitions.

In the context of this description, the term Ngal is used for all human isoforms, known or new, based on nucleic acids or amino acids. These Be ^¬ interfered with comprises are also disclosed in the context of this description, short sequences which originate from the isoforms, for example, immunization sequences. Further comprising also includes homologues, wherein the homologated ^¬ energy at least 80%, preferably more than 90%, most preferably more than 95%. In the case of the nucleic acid sequences, complementary or allelic variants are also included. Furthermore, sequences are included which only represent partial sequences of the explicitly open sequences, for example one exon or several exons, or sequences complementary thereto, with the proviso that, in the case of the nucleic acids, these partial sequences are of sufficient length for hybridization with a nucleic acid according to the invention, have at least 50 bases and, in the case of the proteins or peptides, bind to a protein- or peptide-specific target molecule with at least the same affinity. Furthermore, all nucleic acids hybridizing with nucleic acids according to the invention are included, namely those which are under stringent conditions (for example 5 ° C. to 25 ° C. below the melting temperature; see also JM Sambrook et al., A laboratory anual, Cold Spring Harbor Laboratory Press ( 1989) and EM Southern, J Mol Biol, 98: 503ff (1975)) hybridize. It goes without saying that the invention also includes expression cassettes, ie one or more of the nucleic acid sequences according to the invention with at least one control or regulatory sequence. Such an expression cassette can also comprise a sequence for a known protein, a fusion protein being formed in the course of the translation from a known protein and a protein or peptide according to the invention. Antisense sequences to the above nucleic acid sequences are also included. Finally, RNA as well as correlating DNA and vice versa are included, as are genomic DNA as well as correlated cDNA and vice versa.

In connection with uses according to the invention, the terms Ngal include nucleic acids or proteins or In addition to the full lengths of the sequences disclosed (see also the preceding paragraph), peptides also include partial sequences thereof, with a minimum length of 12 nucleotides, preferably 30 to 90 nucleotides, in the case of the nucleic acids and a minimum length of 4 amino acids, preferably 10 to 30 amino acids , in the case of peptides or proteins.

The terms of detection and / or treatment of tumor diseases, in particular of the tumor types indicated, also include the detection and / or treatment of metastases from primary tumors in other tissues. The term treatment also includes prophylaxis.

An inhibitor is a compound or substance which either inhibits the formation of Ngal or reduces the activity of Ngal formed, based on the Ngal activity in the absence of the inhibitor. In this respect, an inhibitor can be a substance that interferes with the Ngal cascade. On the other hand, an inhibitor can be a substance which binds with the Ngal formed, in such a way that further physiological interactions with endogenous substances are at least reduced.

Mimicry molecules are compounds that simulate the variable region, in particular the binding region of an antibody, and bind to a target molecule in the same place as the underlying antibody.

The term antibody includes polyclonal antibodies, monoclonal antibodies, non-human, human and Humanized antibodies, as well as phage display antibodies, but also chimeric antibodies and anti-idiotypic antibodies, as well as specific fragments of the light and / or heavy chain of the variable region of the underlying antibodies of the above type. The production or production of such antibodies with predetermined immunogens is accordingly Average specialist well familiar and need not be explained in more detail. The term antibody also includes bispecific antibodies. Bispecific antibodies combine a defined immune cell activity with a specific tumor cell recognition, whereby tumor cells are killed. A bispecific antibody binds on the one hand to a trigger molecule of the immune effector cell (eg CD3, CD16, CD64) and on the other hand to antigens of the tumor target cell.

The pharmaceutical preparation of a pharmaceutical composition according to the invention can be carried out in a manner customary in the art. Counter ions for ionic compounds are, for example, Na ⁺ , K ⁺ , Li ⁺ or cyclohexylammonium. Suitable solid or liquid pharmaceutical preparation forms are, for example, granules, powders, dragees, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable "solutions (IV, IP, IM) and preparations with protracted release of active ingredient, in the production of which conventional auxiliaries such as carriers, explosives, binders, coatings, swelling agents, lubricants or lubricants, flavorings, sweeteners and solubilizers are used. The auxiliaries are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, Gela ^¬ tine, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycols and solvents such as sterile water and mono- or polyhydric alcohols, for example glycerin. A pharmaceutical composition according to the invention can be produced by mixing at least one Ngal inhibitor according to the invention in a defined dose with a pharmaceutically suitable and physiologically compatible carrier and, if appropriate, other suitable active substances, additives or auxiliaries with a defined inhibitor dose and preparing the desired dosage form.

Tumor cells express Ngal differentially if normal cells of the same tissue type do not express it. Tumor cells overexpress Ngal specifically or differentially if Ngal is expressed at least twice as much as normal cells of the same tissue.

Cytotoxic components or groups are compounds which directly or indirectly induce apoptosis or lead to necrosis or at least inhibit growth. In addition to radioisotopes (for example 188Re, 213Bi, 99mTc, 90Y, 131J, 177Lu), such groups or compounds can in particular be cytostatics which are used in tumor therapy. Examples include: Alkylant ^'ien (eg mechlorethamine, ifosfamide, chlorambucil, cyclophosphamide, melphalan, alkyl, busulphan, nitrosoureas, carmustine,' lomustine, ustin Se, triazenes, dacarbazine), antimetabolites (eg, folic acid antagonists, methotrexate , Pyrimidine analogs, fluorouracil, fluoro-esoxyuridine, cytarabine, gemcitabine, purine analogs, mercapturin), mitosis inhibitors (e.g. vinca alkaloids, voncristine, vinblastine, paclitaxal, docetaxel, protaxel), epipodophyl-lotidoxins, (e.g. etopos) Antibiotics (e.g. Dactinomycin, daunorubicin, idarubicin, anthracycline, bleomycin, L-asparaginase), platinum complex compounds (e.g. cisplatin), hormones and related compounds (e.g. adrenal cortex steroids, aminogluthetimide, gestagens, estrogens, androgens, anti-estrogens, danalotoxins, tamoxifen, tamoxifen). When such a compound is bound to a ngal-binding substance, the coupling takes place in such a way that the affinity for ngal is reduced by no more than 90%, preferably 50%, based on the substance without a cytostatic group, and the cytostatic effect of the group is not reduced by more than 90%, preferably 50%, based on the compound without substance.

An immunostimulating component is usually a protein or an effective component thereof, which stimulates cells of the immune system. Examples are: cytokines, such as M-CSF, GM-CSF, G-CSF, interferons, such as IFN-alpha, -beta, -ga ma, interleukins such as IL-1 to -16 (except -8), human LIF, Cherαokines such as Rantes, MCAF, MIP-1-alpha, -beta, NAP-1 and IL-8.

A reporter group is an atom, molecule or a compound which, in conjunction with an assay based thereon, enables the detection of the reporter group and the compound or substance thus connected to the reporter group. Examples of reporter groups and associated detection methods are: 32P labeling and intensity measurement using phosphoimager. Many other examples are known to the person skilled in the art and do not need to be listed in detail. A substance that binds to Ngal can be a substance that binds a Ngal protein or a Ngal RNA.

Definitions expanded in the context of the above definition in relation to the narrow sense of the word also include the specific terms in the narrow sense of the word.

Optionally, the indications breast cancer or ovarian cancer can be excluded in certain contexts, particularly in the case of sequence identity of partial sequences.

Examples.

The invention is explained in more detail below on the basis of examples and figures which merely illustrate preferred embodiments. Show it:

FIG. 1: Cancer profiling array for overexpression in uterine tumor tissue,

Figure 2: Quantitative evaluation of the subject of the figure

1,

FIG. 3: various hammerhead ribozymes against Ngal,

FIG. 4: various antisense RNA against Ngal,

FIG. 5: inhibitory RNA (RNAi) against Ngal,

Figure 6: Ngal sequences, amino acid sequence (SEQ ID 1, 6a) with suitable labeling Immunization sequences (SEQ ID 3 and 4) and nucleic acid sequence (SEQ ID 2),

Figure 7: Western blot of lysates and cell culture supernatants expressing different Ngal

Cell lines

FIG. 8: immunohistochemical detection of 2 uterine carcinomas, and

Figure 9: Proliferation assay in a colon tumor line.

Example 1: Ngal overexpression in uterine tumor tissue.

The Ngal coding sequence was labeled with 32P by random hexamer priming and onto a cancer profiling array from Clontech, which contains 240 cDNA library pairs, each pair for one tumor and one

A patient's normal tissue stands. The results are shown in FIG. 1. It can be seen that overexpression takes place in uterine tumor tissue compared to normal tissue. This finding is quantified in FIG. 2. Accordingly, 56% (25 out of 44) of the pairs of uterine tissue examined show an at least 2-fold overexpression of Ngal.

Example 2: Detection of Ngal using antibodies

In this example, the marking of a tumor or its metastases by an anti-Ngal antibody in vivo (Mouse model). An anti-Ngal antibody is labeled with a marker molecule (e.g. radioisotope). 1-2 * 10 ^Λ 6 Ngal-transfected human cells are transplanted into NMRI nude mice. 30 days after the transplant, labeled antibodies are injected into the mice. The control animals are treated with an irrelevant antibody. A few hours after application of the antibody, the animals are sacrificed and tissue sections are made from all organs. These sections are examined for the presence of labeled anti-Ngal 7 antibody.

The anti-Ngal antibodies are polyclonal or monoclonal antibodies against human Ngal protein, by cDNA immunization or conjugated with a carrier protein, grown in rat or rabbit and affinity-purified.

Suitable immunization sequences are shown in FIG. 6a and the sequences SEQ ID 3 and 4. The full-length cDNA (FIG. 6b) can also be used.

Example 3: In the unhistochemical detection of tumor cells.

Primary tumors are isolated from patients with uterine and / or ovarian tumors and prepared as paraffin or frozen sections. These sections are examined with an anti-Ngal antibody for the overexpression of Ngal in tumor cells. The i munhistologische examination with the Ngal antibody shows higher expression of Ngal in the tumor cells relative to surrounding normal tissue ^¬. The investigation is carried out in detail by incubation with the anti-Ngal antibody as the primary Antibodies from rabbit or rat, a biotinylated secondary anti-rabbit or anti-rat antibody and a streptavidin-coupled horseradish peroxidase. The coloring is done with AEC as a chromogenic substrate (red coloring). Counterstaining is done with hemalaun solution (blue staining). Malignant and non-malignant cells can be distinguished, the malignant cells being strongly stained, ie high in Ngal, while the non-malignant cells are only moderately stained.

FIGS. 8a, b show results with anti-Ngal antibodies from the rat in two uterine carcinomas (paraffin sections). Sections with anti-Ngal antibodies are shown below, while the negative controls assigned above are shown with a staining with pre-immune serum from the rat.

Example 4: RNA inhibitors

FIG. 3 shows various hammerhead ribocytes which cut Ngal at the points shown and thus inhibit or at least reduce the activity of any translation products (SEQ ID 5 and "6; Hammerhead).

FIG. 4 shows various antisense sequences for Ngal RNA (SEQ ID 7 and 8).

FIG. 5 shows a PCR product for the generation of Ngal-specific, double-stranded RNAi. PCR primers for the generation of RNAi samples are shown in bold. In capital letters is a T7 RNA polymerase Promoter and lower case letters a Ngal-specific nucleotide sequence shown.

Example 5: Secretion of Ngal

Colon tumor cell lines (HT29) and ovarian tumor cell lines (SK0V3 and OV90) were cultivated in cell culture medium containing 0.5% FCS. After a cultivation period of 1 hour and 12 hours, culture supernatants were removed and concentrated with my filter. After a protein determination, 16 μg / μl protein / career were applied to a 12% BisTris gel. The 25 kD band for Ngal was identified on the blot using Ngal-specific antibodies from rats or rabbits. The results (anti-Ngal antibody from rat) are shown in FIG. 7 (SN = supernatant, lys = lysate). It can be seen that an accumulation of Ngal has taken place in the supernatants of the cell lines HT29 and SKOV3. As a result, Ngal is constitutively secreted.

Example 6: Proliferation assay on a colon tumor cell line.

Cells from the HT29 colon tumor cell line were added without special addition, with EGF (10 ng / ml), with HGF (20 ng / ml) and with Ngal (= otll5) in concentrations of 1 ng / ml, 10 ng / ml, 100 ng / ml , or 200 ng / ml incubated for 72 h. Proliferation was determined using the MTT assay. This assay is based on the reduction of tetrazolium salt to formazan in metabolically active cells. The evaluation was carried out photometrically. It can be seen that Ngal has an effect comparable to EGF or HGF, ie that Ngal extracellularly promotes the proliferation of the tumor cells.

Claims

claims 1. Use of a nucleic acid coding for Ngal and / or a Ngal peptide or protein for the detection of cancer, in particular of ovarian, colon, lung and / or uterine cancer, or for the detection of a risk of the disease of cancer, in particular of the ovarian , Colon, lung and / or uterine cancer, wherein a tissue sample is examined for overtranscription of Ngal RNA or for overexpression of a Ngal protein. 2. Use according to claim 1, wherein a nucleic acid coding for Ngal or a binding substance to Ngal protein or peptide, preferably containing a reporter group, is used, binding said nucleic acid and / or said protein or peptide to the detector substance semi-quantitatively or is detected quantitatively. 3. Use of a Ngal RNA or a Ngal protein or peptide for screening for substances which bind to it, in particular prospective active substances for inhibiting said RNA or said protein or peptide or prospective detector substances, a prospective substance or a mixture of such prospective substances with said RNA or said protein or peptide is contacted, with a binding assay Binding events are determined, and a binding prospective substance is selected, if necessary after deconvoluting. Use of a substance inhibiting or binding to Ngal, preferably a substance which at the same time does not inhibit the secretion of Ngal, for the production of a pharmaceutical composition for the treatment of cancer, in particular of ovarian, colon, lung and / or uterine cancer. 5. Use according to claim 4, wherein the substance is an antibody which is obtained by immunizing a non-human mammal with a Ngal peptide or protein, or with Ngal cDNA, or with cells transiently or stably transfected with Ngal cDNA, in particular tumor cell lines, NIH3T3, CHO , COS, or with endogenous Ngal-expressing tumor cells or with Ngal produced in insect cells, or a phage display antibody. 6. Use according to claim 4, wherein the substance is a facial expression compound of an antibody against an Ngal peptide or protein. 7. Use according to claim 4, wherein the substance is an aptamer, an antisense RNA, or a ribozyme. 8. Use according to any one of / claims 4 to 7, wherein the substance additionally carries a cytotoxic and / or immunostimulating component. 9. Use according to one of claims 4 to 8, wherein the pharmaceutical composition is prepared for systemic or local application in tissue containing tumor cells. 10. A method for the diagnosis of cancer, in particular of ovarian, colon, lung and / or uterine cancer, wherein a detector substance in one Embodiment is applied with a reporter group in the tissue to be examined, the tissue to be examined is then subjected to a detection method stage which is sensitive to the reporter group, and in the case of detection of a defined minimum value of the reporter group in the tissue, the tissue is qualified as containing tumor cells. 11. A method for the treatment of cancer, in particular ovarian, colon, lung and / or uterine cancer, wherein a pharmaceutical composition according to one of claims 4 to 9 is administered to a patient in a physiologically effective dose. 12. Use of a Ngal protein in a screening process to find substances that modulate the secretion of Ngal. 13. Use according to claim 12, wherein cells expressing Ngal are cultivated in a medium, incubation being carried out before or during the cultivation with a prospective secretion-inhibiting substance or with a mixture of such substances, the medium being analyzed for Ngal after a defined cultivation period is, optionally after separating the medium from the cells, and the substance, if necessary after deconvolution, is selected if the amount of detected Ngal in the medium falls below a defined limit. 14. Use according to claim 13, wherein the defined limit value is determined by cultivation under the same conditions, but without incubation with a prospective secretion-inhibiting substance. 15. Use of a method according to one of the Claims 12 to 14 selected substance for the manufacture of a pharmaceutical composition for the treatment of cancer, in particular ovarian, colon, lung and / or uterine cancer. 16. Use of a Ngal protein in a screening process for finding a Ngal but not inhibiting the secretion inhibiting substance, wherein Ngal expressing cells cultured in a medium who ^¬, wherein one or while prior to culturing according to claim 3 with a selected substance, or with Mixture of such substances is incubated, the Medium is analyzed for Ngal after a defined cultivation period, optionally after separation of the medium from the cells, and the substance, if appropriate after deconvolution, is selected if the amount of Ngal detected in the medium exceeds a defined limit value. 17. Use according to claim 16, wherein the defined limit value is determined by cultivation under the same conditions, but without incubation with a prospective, secretion-inhibiting substance. 18. Use of a substance selected by a method according to one of claims 12, 13 or 14 for the production of a pharmaceutical composition for the treatment of cancer, in particular ovarian, colon, lung and / or uterine cancer.