WO2003047571A2

WO2003047571A2 - Use of a kmo inhibitor for producing a pharmaceutical composition

Info

Publication number: WO2003047571A2
Application number: PCT/DE2002/004309
Authority: WO
Inventors: Esmeralda CASTANOS-VÉLEZ HEIDEN; Bernd Hinzmann; Andreas Rump; Edgar Dahl; Thomas Specht; Karin Blechschmidt; Rosemarie Lichtner; Kasper GRIT; Matthias Reule; André ROSENTHAL; Gunda Herberth; Katrin Sparbier
Original assignee: Metagen Pharmaceuticals Gmbh; Andreas Rump
Priority date: 2001-11-28
Filing date: 2002-11-20
Publication date: 2003-06-12
Also published as: DE10159215A1; AU2002351693A1; WO2003047571A3

Abstract

The invention relates to the use of a KMO inhibitor for producing a pharmaceutical composition used in the treatment of cancers and to the use of a substance that binds to KMO for producing a pharmaceutical composition for detecting tumor cells.

Description

Use of a KMO inhibitor for the manufacture of a pharmaceutical composition

Field of the Invention

The invention relates to the use of a KMO inhibitor for the production of a pharmaceutical composition.

Background of the Invention and Prior Art

KMO is a NADPH-dependent monooxygenase that catalyzes the reaction of L-kynurenine to L-3-hydroxykynurenine in tryptophan metabolism [see Bertazzo, A., Ragazzi, E., Biasiolo, M., Costa, C.V. and Allegri, G,; Enzyme activities involved in tryptophan metabolism along the kynurenine pathway in rabbits. Biochim Biophys Acta 1527 (2001) 167-75.]. KMO is also called kynurenine 3-monooxy-genase or kynurenine 3-hydroxylase

(EC1.14.13.9s). Human KMO consists of 486 amino acids and is under accession no. NM__003679 known.

A large number of publications deal with the function of KMO and its relevance in connection with diseases [see Stone, TW: Kynurenines in the CNS: from endogenous obscurity to therapeutic i portance. Prog Neurobiol 64 (2001) ^• 185-218, as well as the literature mentioned therein]. The publications known in this respect deal with the important role of KMO in connection with neurodegenerative diseases, such as epilepsy or Huntington's disease. It was shown that the product of the catalytic reaction of the KMO, 3-hydroxykynurenine, which Promotes neurodegeneration, while the substrate for KMO, L-kynurenine, has neuroprotective properties. Since the inhibition of KMO leads to the accumulation of the neuroprotective L-kynurenine, many investigations have been directed towards the development of potent KMO-specific inhibitors. In this regard, reference is also made to the Stone literature section, as stated above, and the literature references mentioned therein.

In the Davydov, D.R. : Microsomal monooxygenase in apoptosis: another target for cytochrome c signaling? Trends Biochem Sei 26 (2001) 155-60, KMO is also addressed in other contexts, namely in connection with apoptosis as a target for cytochrome C signaling.

Technical problem of the invention

The invention is based on the technical problem of specifying a pharmaceutical composition for the diagnosis and treatment of cancer.

Fundamentals of the invention and preferred exemplary embodiments.

To solve this technical problem, the invention teaches the use of a KMO inhibitor for the production of a pharmaceutical composition for the treatment of

Cancer and the use of a KMO-binding substance for the manufacture of a pharmaceutical composition for the detection of tumor cells. The invention is based on the knowledge that KMO is expressed or overexpressed in tumor cells compared to normal cells of the same tissue. On the one hand, this allows KMO to be used as a marker for identifying tumor cells. On the other hand, the inhibition of KMO offers the possibility, inter alia, to intervene in the tumor-related metabolism via NAD and thus ultimately to disrupt the tumor cell-specific metabolism and to contribute to the death or at least growth inhibition of the tumor cells.

If a KMO-binding substance is used in a pharmaceutical composition for the detection of tumor cells, it is preferred if the KMO-binding substance

Substance is a KMO inhibitor. The uses according to the invention are particularly suitable for the treatment or diagnosis of breast cancer or uterine cancer.

In principle, the inhibition can take place at the protein level or nucleic acid level. It is therefore preferred if the inhibitor is selected from the group consisting of a) inhibitor of the KMO protein, b) inhibitor of the KMO-RMA. In particular, the inhibitor of the KMO protein can be a molecule according to Formula I.

Formula I.

where X = H, N, NH, OY1, SY1, or NY1Y2, where Yl and Y2 can be the same or different and H or Cl-8 are alkyl, aryl or aralkyl, optionally substituted, where Z = COOR1, Cl-8-aryl, optionally substituted, or a group selected from "furan, thiofuran, azole, isoazole, diazole, isodiazole, traizole, dithiol, oxathiol, isoxalzol, oxazole, thiazole, isothiazole, oxadiazole, tetrazole, oxatriazole, di- oxazole, oxathiazole, thiatriazole, and H or Cl-4 alkyl or shark substituted above groups ", where Rl = H or Cl-8 alkyl, aryl or aralkyl is optionally substituted, where R2 = F, Cl, Br, J , Cl-8-alkyl, aryl, or aralkyl, optionally substituted, OR3, NO, or NR4R5, where R3 = H, Cl-8-alkyl, aryl, or aralkyl, optionally substituted, R4 and R5 = H, C2-8-alkyl, aryl, or aralkyl, optionally substituted, where R3 to R5 can be the same or different, where R2 can be single, double or triple and can be the same or different if they are more than one, (ortho-, m eta- and / or para-), where there can be a single or double bond, where there can be a single bond or no bond, and the aromatic ring of formula I can contain one or more heteroatoms, in particular N, optionally one or more free valences of formula I can be a reporter group and / or a cytotoxic group and are otherwise H

Compounds of the formula I are particularly suitable, where Z = COOMe or COOH / X = OH or NH2, 0 is a double bond and R2 is selected from: H, 2-C1, 2-N02, 3-Cl, 3-Br, 3- F, 4-C1, 4-Br, 4-F, 4-Me, 2,3-di-Cl, 2,3-di-F, 3,4-di-Cl, 3,4-di-F, 3-C1-4-F, 3-Me-4-Cl, 3-N02-4-C1. Also particularly suitable are compounds of the formula I, where Z = COOMe, COOH or a group selected from "furan, thiofuran, azole, isoazole, diazole, isodiazole, traizole, dithiol, oxathiol, isoxalzol, oxazole, thiazole, isothiazole, oxadiazole, tetrazole, oxatriazole, dioxazole, oxathiazole, thiatriazo'l", X = = N is with as a single bond and R2 is selected from: H, 2-C1, 2-N02, 3-C1, 3-Br, 3-F, 4-C1, 4-Br, 4-F, 4-Me, 2 , 3-di-Cl, 2,3-di-F, 3,4-di-Cl, 3,4-di-F, 3-C1-4-F, 3-Me-4-Cl, 3-N02 -4-C1.

In a further embodiment of the invention, the inhibitor of the KMO protein is a molecule of the formula II

Formula II

where ZI and Z2 can be the same or different and F, Cl, Br, J, Cl-8-alkyl, -aryl, or -aralkyl, optionally substituted, are OR3, NO- or NR4R5, where R3 = H, Cl- 8-alkyl, aryl or aralkyl, optionally substituted, R4 and R5 = H, Cl-8-alkyl, aryl, or aralkyl, optionally substituted, where R3 to R5 can be identical or different, where ZI and Z2 are in each case single, double or triple and, if they are present several times, can be the same or different (ortho-, eta- and / or para-), where the thiazolidine group can also be 4,5 dihydrothiazole or thiazolidine, and optionally one or several free valences of the formula I can be a reporter group and / or a cytotoxic group and are otherwise H. In the case of particularly suitable compounds of the formula II, ZI = H, 4-Me, 4-C1, 4-OMe, 4NH2, 3-C1-4-C1, 3-OMe-4-OMe and Z2 = H, 4- C1, 4-Me, 4-OMe, 3-N02, 3-C1-4-C1, 2-F-5-CF3.

As an alternative to the above relatively small molecules, the inhibitor of the KMO protein can be an antibody against (human) KMO. Such antibodies can be polyclonal or monoclonal. They can be obtained in a customary manner by immunizing non-human mammals, for example rodents, with human KMO or with peptides which are specific to human KMO. However, it is not necessary to use a complete antibody, rather only the variable part can be used. Antibodies, complete or fragmentary, can come from non-human organisms and can be humanized or represent chimeric antibodies. It is also possible to produce synthetic substances that mimic the binding region of an antibody, i.e. on the one hand have corresponding binding sites and on the other hand fix these binding sites in a defined spatial orientation to one another, corresponding to an antibody.

In a further embodiment of the invention, an inhibitor of the KMO-RNA is used, which is selected from the group consisting of "ribozyme, aptamer and antisense nucleic acid against KMO".

The embodiment of the invention is preferably used as a pharmaceutical composition for the treatment of cancer, in which KMO is specifically expressed or overexpressed by tumor cells. In Based on these relationships, it may be advisable to take a sample from a tissue that is identified as tumor tissue using other methods before the treatment and to examine the tissue sample for expression or overexpression of KMO. Alternatively, a pharmaceutical composition according to the invention can be used to test for KMO dependency in vivo. If expression or overexpression of KMO compared 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 KMO, but normal cells of the same tissue type are not, it can be recommended that the KMO-binding substance also carries a cytotoxic component. This ultimately leads to the fact that almost exclusively tumor cells are killed, while normal cells are almost completely retained in the tissue. If a cytotoxic component is used, it can be recommended that the pharmaceutical composition be prepared for local application in tissue containing tumor cells, for example for injection.

In the embodiment of the invention for the detection of

Tumor cells preferably carry the KMO-binding substance additionally with a reporter group. By using an assay tailored to the reporter group, it can be determined whether or to what extent KMO is expressed or overexpressed in cells of the examined tissue. In this way it can easily be determined whether tissue contains KMO-dependent tumor cells. It is also possible to determine whether one with other methods identified tumor tissue is KMO-dependent and is suitable for treatment with a pharmaceutical composition according to the invention.

Finally, the invention relates to a method for diagnosing a cancer, a pharmaceutical composition according to the invention being applied in the embodiment with a reporter group to the tissue to be examined, the tissue to be examined then being subjected to a detection method step which is sensitive to the reporter group, and in the case of the 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 a tumor disease, a pharmaceutical composition according to the invention being given to a patient. The explanations given in this description apply analogously to these methods according to the invention.

Definitions.

KMO is also called kynurenine 3-monooxygenase or kynurenine 3-hydroxylase. The protein is known under the accession number NM_003679.

A KMO inhibitor is a compound or substance which either inhibits the formation of KMO or reduces the KMO activity formed, based on the KMO activity in the absence of the KMO inhibitor. In this respect, a KMO inhibitor can be a substance that interferes with the KMO cascade. On the other hand, it can be a KMO inhibitor be a substance which forms a bond with the KMO formed, in such a way that the KMO can no longer catalyze the reaction from L-kynurenine to 3-hydroxykynurenine or only with a reduced conversion rate. In this respect, mimicry molecules of L-kynurenine in particular are considered, but not the latter itself. Mimicry molecules are compounds which either completely prevent further reactions or lead to physiologically inactive catalytic products in the downstream region of the kynurenine pathway of tryptophan metabolism. Typical examples of this are shown in formula I.

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 galenical forms of preparation are, for example, granules, powders, dragees, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions (IV, IP, I.) and preparations with a protracted active ingredient -Release, in the production of which customary auxiliaries such as carriers, disintegrants, binders, coating agents, swelling agents, lubricants or lubricants, flavorings, sweeteners and solubilizers are used. As auxiliary substances magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and plant oils such as cod liver ^¬ Liche, sunflower, peanut or Se Samoel, 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 in that at least one KMO inhibitor used according to the invention is mixed in a defined dose with a pharmaceutically suitable and physiologically compatible carrier and, if appropriate, further suitable active substances, additives or auxiliaries with a defined inhibitor dose and is prepared for the desired dosage form.

An inhibitor of the KMO protein is a substance or compound which binds to KMO and reduces its activity towards KMO in the absence of the inhibitor. The KMO-RNA inhibitor refers to compounds or substances which inhibit transcription, bind RNA, cut if necessary, and / or inhibit translation.

Substituted Cl-8-alkyl, aryl, or aralkyl carry a chemical group instead of one or more hydrogen atoms. Examples include OH, ether, ester, primary amine, secondary amine, tertiary amine, carboxyl, nitro and halogen.

The term antibody encompasses both monoclonal antibodies and polyclonal antibodies.

Tumor cells express KMO specifically when normal cells of the same tissue type do not express KMO. Tumor cells overexpress KMO specifically if KMO is expressed in at least double the amount compared to normal cells of the same tissue.

Cytotoxic components or groups are compounds which directly or indirectly induce apoptosis or at least inhibit growth. Such groups or Compounds can be cytostatics in particular, which are used in tumor therapy. Examples of these are: alkylating agents (for example mechlorethamine, ifosfamide, chlorambucil, cyclophosphamide, melphalan, alkylsulfonates, butulfan, nitrosoureas, carmustine, lomustine, semustin, triazenes, dacarbazine), antimetabolites (for example folic acid antagonists, pyrimidine) -Analogues, fluorouracil, fluorodesoxyuridine, cytarabine, gemcitabine, purine analogues, mercaptopurine), mitosis inhibitors (e.g. vinca alkaloids, voncristin, vinblastine, paclitaxal, docetaxel), epipodophyllo-toxins (e.g. etoposide, yeastipodin, eg, antibiotics, eg. Daunorubicin, idarubicin, anthracycline, bleomycin, L-asparaginase), platinum complex compounds (eg cisplatin), hormones and related compounds (eg adrenal gland steroids, aminogluthetides, progestogens, estrogens, androgens, anti-oestrogens, tamoxifen, steriodanalogens). When such a compound is bound to a substance that binds to KMO, the coupling takes place in such a way that the affinity for KMO 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.

A reporter group is an atom, molecule or a compound which, in conjunction with an assay placed 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 average person skilled in the art and do not require a detailed list. A substance that binds to KMO can be a substance that binds a KMO protein or KMO RNA.

Examples.

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

1: test results for overexpression of KMO in breast tumor tissues from patients,

2: test results for overexpression of KMO in uterine tumor tissues from patients,

3: test results for the expression or overexpression of KMO in cell lines which are derived from different types of tumor,

4a-f: compounds which inhibit KMO protein,

5: two hammerhead ribozymes which cut KMO mRNA.

Example 1: Overexpression in breast tumor

The KMO coding sequence was labeled with 32P by means of the rando hex priming and hybridized to a "Cancer profiling array" from Clontech, which contains 240 cDNA library pairs, each pair comprising tumor and Represents normal tissue from a single patient. The signal intensities obtained were determined using a phosphor imager and the tumor / normal ratio calculated for each pair. The results obtained are shown in FIG. 1. It can be seen that 18 out of 53, ie 34%, of the breast tumors show at least two-fold overexpression of KMO. Within the subgroup of invasive ductal carcinomas, 43% of the tumors showed at least two-fold overexpression.

Example 2: Overexpression in Uterine Tumor

The KMO coding sequence was labeled with 32P by means of the randorn hexmer priming and hybridized to a "cancer profiling array" from Clontech which contains 240 cDNA library pairs, each pair representing tumor and normal tissue from a single patient. The signal intensities obtained were quantified using a phosphor imager and tumor / normal ratios were calculated. The result is shown in FIG. 2. 20 of 43, i. e. 46% of the uterine organs showed at least two-fold overexpression of KMO. Some of the tumors even showed more than tenfold overexpression, the maximum being almost thirtyfold in uterine adenocarcinoma.

Example 3: Examination of breast tumor cell lines

KMO-specific oligonucleotide primers were generated and used for quantitative PCR using first strand cDNA from various cell lines as a template. At the time the mRNA was isolated, these cell lines were either confluent (c) or subconfluent (sc). With one exception, cell lines derived from non-breast tissue (p / t = prostate tumor, k / n = normal keratinocytes, 1 / t = lung tumor) showed no KMO overexpression (see FIG. 3). In contrast, four out of six breast tumor lines (c / t = breast tumor) showed significant, ie up to fiftyfold, overexpression compared to normal breast cell lines (b / n = breast normal). This was independent of the cultivation status. This means that KMO overexpression is not only associated with proliferation or tumor growth, but is a specific characteristic of breast tumors, among other things.

Example 4

Various compounds are shown in FIG. 4 which are suitable as inhibitors of the KMO protein. Because of their structure related to L-kynurenine, these compounds bind to KMO competitively with L-kynurenin and thus block the reaction of L-kynurenine to 3-hydroxykynurenine in the cell.

Example 5: KMO RNA inhibitors

Seq-ID 1 shows a usable antisense nucleic acid (phosphothioate oligo, 20mer). This binds to KMO RNA and inhibits translation.

In the figure 5, two ge for the inhibition of KMO mRNA ^¬ are suitable hammer ribozymes shown. The sequences for this are shown in Seq-ID 2 and 4. The sequence regions in which the interfaces of the ribozymes are located are in the sequences Seq-ID 3 and 5 reproduced. The interfaces are identified by an arrow in FIG. 5. RNA cut with these ribozymes cannot be translated into KMO protein.

Example 6: KMO antibody

Polyclonal KMO antibodies were generated in Gallus gallus by immunization with one or more of the KMO-specific peptides of the sequences Seq-ID 6-8, which had been conjugated with a carrier protein. Sera were removed and the antibodies contained therein were affinity purified using the immobilized three peptides mentioned.

Example 7: In-situ hybridization of breast tumor tissue

3 arrays with human breast tissue were used, which were created with tissue samples taken from human patients. Each of these arrays contains thin sections from 15 different breast tumors as well as from paired normal tissue, which was obtained from the surroundings of the respective tumor.

A radioactively labeled probe was used for hybridization, which covers the complete coding region of the KMO gene, but does not contain any region which could cross-react with other genes.

In 7 out of 45 cases there was a significant overexpression of KMO compared to normal tissue. Example 8: In-situ hybridization of prostate tumor tissue

An array commercially available from BioCat was used, which was created using tissue samples taken from human patients. Such an array contains thin sections from 55 different adenocarcinomas of the prostate as well as 2 tissue sections from normal prostate tissue.

Again, a radioactively labeled probe was used for hybridization, which covers the complete coding region of the KMO gene, but does not contain any region which could cross-react with other genes.

In 47% of the tumor tissue sections there was a pronounced expression of KMO compared to normal tissue, whereas no expression was measurable in the normal tissue sections.

Example 9: Cell culture-based assay with tumor cell lines

In order to test the influence of the KMO inhibitor 3, 4-dichlorobenzoyl-alanine (PNU156561) on tumor cells in vitro, cell lines were selected which had previously been shown by quantitative PCR to express KMO strongly at the RNA level, for example ZR75- 1 or T47D. Various amounts of the KMO inhibitor were added to these cell lines and the behavior of the cells with regard to proliferation and apoptosis was tested in standard assays. In a crystal violet assay (cytotoxicity assay), for example, a strongly dose-dependent inhibition of proliferation was found for the cell line ZR75-1. While absorbance values of 0.58 and 0.54 were obtained with control samples (without PBS and with PBS), the values for 1 uM, 10 μM and 50 uM of the inhibitor were 0.52, 0.48 and 0, 10th These values were confirmed when an additional 0.5 µM Kynurenine was added.

Example 10: Determination of the Effect of a KMO Inhibitor on Human Tumors in Animal Experiments

To determine the influence of the KMO inhibitor from example 9 on the tumor development to be tested in vivo, nude mice are each given 10 ⁶ cells of the prostate tumor cell line PC3. This can be done by subcutaneous injection or by orthotopic injection into the prostate. 3 days after the injection, some of the animals (rest: control group) were given a defined dose of the inhibitor intraperitoneally, for example 400 mg / kg / day, daily. The influence of the inhibitor on tumor development is quantified by comparing the tumor growth rates between the test group and the control group. The first orienting results indicate that an inhibition of proliferation also takes place in vivo.

Claims

Claims:

1. Use of a KMO inhibitor for the manufacture of a pharmaceutical composition for the treatment of cancer.

2. Use of a substance that binds to KMO for the production of a pharmaceutical composition for the detection of tumor cells.

3. Use according to claim 2, wherein the KMO-binding substance is a KMO inhibitor.

4. Use according to one of claims 1 to 3, for the treatment or diagnosis of breast cancer, prostate cancer or uterine cancer.

5. Use according to one of claims 1 to 4, wherein the inhibitor is selected from the group consisting of: a) inhibitor of the KMO protein, b) inhibitor of the KMO RNA

6. Use according to one of claims 1 to 5, wherein the inhibitor of the KMO protein is a molecule of formula I.

Formula I.

where X = H, N, NH, 0Y1, SY1, or NY1Y2, where Yl and Y2 may be the same or different and H or Cl-8 are alkyl, aryl or aralkyl, optionally substituted, where Z = COOR1, Cl-8-aryl, optionally substituted, or a group selected from "furan, thiofuran, azole, isoazole, diazole, isodiazole, traizole, dithiol, oxathiol, isoxalzol, oxazole, thiazole, isothiazole, oxadiazole, tetrazole, oxatriazole, dioxazole, Oxathiazole, Thiatria- zol, and H or Cl-4 alkyl or Hai substituted above groups ", where Rl = H or Cl-8 alkyl, aryl or aralkyl is optionally substituted, wherein R2 = F, Cl, Br, J , Cl-8-alkyl, -aryl, or -aralkyl, optionally substituted, is OR3, NO- or NR4R5, where R3 = H, Cl-8-alkyl, -aryl, or -aralkyl, optionally substituted, R4 and R5 = H, Cl-8-alkyl, -aryl, or -aralkyl, optionally substituted, where R3 to R5 can be the same or different, where R2 is single, double or triple and, in the case of multiple occurrence, be the same or different can, being can be a single or double bond, where can be a single bond or no bond, wherein the aromatic ring of formula I can contain one or more heteroatoms, in particular N, wherein optionally one or more free valences of formula I can be a reporter group and / or a cytotoxic group and are otherwise H.

7. Use according to one of claims 1 to 5, wherein the inhibitor of the KMO protein is a molecule of the formula II

Formula II

where ZI and Z2 may be the same or different and F, Cl, Br, J, Cl-8-alkyl, aryl, or aralkyl, optionally substituted, are OR3, NO _: or NR4R5, where R3 = H, Cl- 8-alkyl, aryl or aralkyl, optionally substituted, R4 and R5 = H, Cl-8-alkyl, aryl or aralkyl, optionally substituted, it being possible for R3 to R5 to be identical or different , where ZI and Z2 are each single, double or triple and may be the same or different if they are present several times, the thiazole group also being 4.5 dihydrothiazole or thiazolidine, and where optionally one or more free valences of the formula I can be a reporter group and / or a cytotoxic group and are otherwise H.

8. Use according to one of claims 1 to 5, wherein the inhibitor of the KMO protein is an antibody or a facial expression compound against KMO.

9. Use according to one of claims 1 to 5, wherein the inhibitor of the KMO RNA is selected from the group consisting of "ribozyme, aptamer and antisense nucleic acid against KMO".

10. Use according to one of claims 1 to 9, wherein tumor cells specifically express or overexpress KMO.

11. Use according to one of claims 1 to 10 in the

Embodiment in which the tumor cells express KMO specifically, the KMO-binding substance additionally carrying a cytotoxic component.

12. Use according to one of claims 1 to 11, wherein the pharmaceutical composition is prepared for local application in tissue containing tumor cells.

13. Use according to one of claims 1 to 12, wherein the KMO-binding substance additionally carries a reporter group.

14. A method for diagnosing a cancer, wherein a pharmaceutical composition according to any one of claims 1 to 13 in the embodiment with a reporter group in the tissue to be examined, optionally after

10 removal of a tissue sample, is applied, the tissue to be examined then being 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

15 tissue containing the tissue as tumor cells and / or the tumor is specifically expressed as KMO or overexpressing.

15. A method for the treatment of a person suffering from cancer, optionally taking a tissue sample from tumor tissue and examining it for expression or overexpression of KMO, the person, if appropriate based on a positive result

25 of the examination, a pharmaceutical composition according to one of claims 1 to 13, optionally in the embodiment with cytotoxic component, is presented, for example by local injection into the tumor tissue.

30