Sensitizing Cells for Apoptosis by Selectively Blocking Cytokines

Abstract

The invention refers to the use of a cytokine antagonist which modulates the expression and/or the function of a cytokine, particularly a Th2 helper cell cytokine, in a cell and causes the down-regulation of anti-apoptotic proteins in said cell through the cytokine modulation for sensitizing cells for apoptosis. In particular, the cells that can be treated with the cytokine antagonists are drug-resistant cancer cells which fail to undergo apoptosis.

1 . Use of a cytokine antagonist which modulates the expression and/or the function of a cytokine in a cell for the down-regulation of a cell death preventing protein in a cell. 
     
     
         2 . The use according to  claim 1 , wherein the cell is sensitized for cell death. 
     
     
         3 . The use according to  claim 1  or  2 , wherein the cell is a cancer cell. 
     
     
         4 . The use according to any of  claims 1  to  3 , wherein the cytokine is selected from the group consisting of IL-4, IL-5, IL-6, IL-10 and IL-13, and combinations thereof, preferably IL-4, IL-10 and IL-13, and combinations thereof. 
     
     
         5 . The use according to any of  claims 1  to  3 , wherein the cell death is caused by apoptosis and the cell death preventing protein is an anti-apoptotic protein selected from the group consisting of Bcl-2, cFLIP, Mcl-1, A1, BOO, NR-13, sentrin, TOSO, CPAN, PED, DFF45, NAP, XIAP, cIAP-1, cIAP-2, ML-IAP, MAP, BIRC5, TIAP, Apollon and fortilin, preferably Bcl-2, Bcl-x L , PED and cFLIP, and combinations thereof, most preferably Bcl-2 and/or Bcl-x L . 
     
     
         6 . The use according to any of  claims 1  to  5 , wherein the cytokine antagonist is selected from the group consisting of a transcriptional regulator of the cytokine/cytokine receptor gene, an antisense nucleic acid molecule that is complementary to a region of the cytokine/cytokine receptor gene, a dsRNA molecule that is complementary to the cytokine/cytokine receptor mRNA, a ribozyme that cleaves the cytokine/cytokine receptor mRNA, a translational regulator of the cytokine/cytokine receptor mRNA, an aptamer, which bind to the cytokine and/or cytokine receptor and prevents or disrupts the interaction between the cytokine and its receptor, an antibody that binds to the cytokine/cytokine receptor, a receptor, a fragment or derivative thereof, of the cytokine, preferably CD124, CD132, IL-13Rα-2 and IL-10Rα, a cytokine trap, and a cytokine mutein 
     
     
         7 . The use according to  claim 6 , wherein the cytokine antagonist is an antibody that binds to the cytokine/cytokine receptor. 
     
     
         8 . The use according to  claim 7 , wherein the antibody is an antibody that binds to IL-4, IL-10 or IL-13, and combinations thereof. 
     
     
         9 . The use according to any of  claims 1  to  8 , wherein the cytokine antagonist is delivered to the proximity of or into the target cell. 
     
     
         10 . The use according to  claim 9 , wherein the cytokine antagonist is delivered via a retroviral vector. 
     
     
         11 . A method for the down-regulation of a cell death preventing protein in a cell, the method comprising
 (a) providing a sample of tissue or cells from a subject   (b) contacting the cell or the sample with a cytokine antagonist according to any of  claims 6  to  8 .   
     
     
         12 . The method according to  claim 11 , wherein the cell is a cancer cell. 
     
     
         13 . Use of a cytokine antagonist, optionally in combination with radiation therapy, for the manufacture of a medicament for the treatment of cancer. 
     
     
         14 . Use of a cytokine antagonist, optionally in combination with at least one active compound, for the manufacture of a medicament for the treatment of cancer. 
     
     
         15 . The use according to  claim 14 , wherein the active compound is selected from the group consisting of antimetabolites, preferably cytarabine, fludarabine, 5-fluoro-2′-deoxyuiridine, gemcitabine, hydroxyurea or methotrexate; DNA-fragmenting agents, preferably bleomycin, DNA-crosslinking agents, preferably chlorambucil, cisplatin, cyclophosphamide or nitrogen mustard; intercalating agents preferably adriamycin (doxorubicin) or mitoxantrone; protein synthesis inhibitors, preferably L-asparaginase, cycloheximide, puromycin or diphteria toxin; topoisomerase I poisons, preferably camptothecin or topotecan; topoisomerase II poisons, preferably etoposide (VP-16) or teniposide; microtubule-directed agents, preferably colcemid, colchicine, paclitaxel, vinblastine or vincristine; kinase inhibitors preferably flavopiridol, staurosporin, STI571 (CPG 57148B) or UCN-01 (7-hydroxystaurosporine); miscellaneous investigational agents, preferably PS-341, phenylbutyrate, ET-18-OCH 3 , or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols preferably quercetin, resveratrol, piceatannol, epigallocatechine gallate, theaflavins, flavanols, procyanidins, betulinic acid; hormones preferably glucocorticoids or fenretinide; hormone antagonists, preferably tamoxifen, finasteride or LHRH antagonists; plant-derived cytostatics (from Viscum and derivatives); alcaloids preferably vindesine; podophyllotoxins preferably vinorelbin; alkylants preferably nimustrine, carmustrine, lomustine, estramustrine, melphalam, ifosfamide, trofosfamide, bendamustine, dacarbazine, busulfane, procarbazine, treosulfane, tremozolamide, thiotepa; cytotoxic antibiotics preferably aclarubicine, daunorubicin, epirubicine, idarubicine, mitomycine, dactinomycine; antimetabolites like folic acid analogs preferably methotrexate, purine analogs preferably cladribin, mercaptopurin, tioguanine and pyrimidine analogs preferably cytarabine, fluorouracil, docetaxel; other antineoplastic, platinum compounds preferably thioplatin, carboplatin, oxaliplatin; amsacrine, irinotecane, interferon-α, tretinoine, hydroxycarbamide, miltefosine, pentostatine, aldesleukin; antineoplastic compounds derived from organs, e.g. monoclonal antibodies preferably trastuzumab, rituximab, or derived from enyzmes preferably pegaspargase; endocrine effecting antineoplastic compounds belonging to hormones, e.g. estrogens preferably polyestradiol, fosfestriol, ethinylestradiol, gestagens preferably medroxyprogesterone, gestonoroncaproat, megestrol, norethisterone, lynestrenol, hypothalamus hormones preferably triptorelin, leuproreline, busereline, gosereline, other hormones preferably testolactone, testosterone; endocrine effecting antineoplastic compounds belonging to hormone antagonists, e.g. antiestrogens preferably toremifen; antiandrogens preferably flutamide, bicalutamide, cyproterane; endocrine effecting antineoplastic compounds belonging to enzyme inhibitors preferably anastrol, exemestane, letrozol, formestane, aminoglutethimide, all of which can be occasionally administered together with so-called protectives preferably calciumfolinat, amifostin, lenograstin, molgromostin, filgrastin, mesna or so-called additives preferably retinolpalmitate, thymus D9, amilomer. 
     
     
         16 . The use according to  claim 15 , wherein the active compound is selected from the group consisting of paclitaxel, cisplatin, and doxorubicin. 
     
     
         17 . The use according to  claim 14 , wherein the active compound is a death receptor agonist. 
     
     
         18 . The use according to  claim 17 , wherein the death receptor agonist is a death receptor ligand selected from the group consisting of TNF-α, TNF-β, LT-β, TRAIL, CD95 ligand, TRAMP ligand, DR6 ligand, and fragments and derivatives thereof. 
     
     
         19 . The use according to  claim 17 , wherein the death receptor agonist is an antibody against a death receptor, a derivative or fragment thereof, selected from the group consisting of anti-CD95 antibody, anti-TRAIL-R1 antibody, anti-TRAIL-R2 antibody, anti-DR6 antibody, anti-TNF-R1 antibody and anti-TRAMP antibody. 
     
     
         20 . The use according to  claim 14 , wherein the active compound is a negative regulator of anti-apoptotic proteins, preferably IAPs. 
     
     
         21 . The use according to any of  claims 13  to  20 , wherein the cancer to be treated is selected from the group consisting of neuroblastoma, intestine carcinoma preferably rectum carcinoma, colon carcinoma, familiary adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tong carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, follicular thyroid carcinoma, anaplastic thyroid carcinoma, renal carcinoma, kidney parenchym carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, testis carcinoma, breast carcinoma, urinary carcinoma, melanoma, brain tumors preferably glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeolid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, hepatocellular carcinoma, gall bladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyo sarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma and plasmocytoma. 
     
     
         22 . The use according to any  claim 21 , wherein the cancer to be treated is selected from the group consisting of thyroid carcinoma, breast carcinoma, lung carcinoma, prostate carcinoma and colon carcinoma. 
     
     
         23 . The use according to any  claim 21 , wherein the cancer to be treated is thyroid carcinoma. 
     
     
         24 . A medicament for the treatment of cancer, comprising a cytokine antagonist, optionally in combination with at least one active compound, and a pharmaceutically acceptable carrier. 
     
     
         25 . The use of a cytokine antagonist for diagnosing and monitoring the cancer disease of a subject, comprising
 (a) providing a body fluid sample or a sample of tissue or cells from a tumor of a subject   (b) contacting the sample with a labeled probe that binds to a cytokine nucleic acid and/or with an antibody that binds to a cytokine   (c) determining the expression level of the cytokine in the tissue or cells and comparing the expression level with healthy control cells, and   (d) correlating a better prognosis for the subject with a low ratio of cytokine expression when compared to the expression level in healthy control cells.   
     
     
         26 . A diagnostic kit containing at least one cytokine antagonist, optionally in combination with suitable buffers, enzymes and other compounds. 
     
     
         27 . The use according to any of  claims 1  to  10 , wherein the cell is a non-lymphoid and a non-myeolid cancer cell. 
     
     
         28 . The use according to  claim 27 , wherein the cytokine is IL-4 and/or IL-10 and/or IL-13. 
     
     
         29 . The use according to  claim 27  or  28 , wherein the cytokine is not produced by a lymphoid or a myeloid cell. 
     
     
         30 . The use according to  claim 29 , wherein the cytokine is autocrinely produced by the non-lymphoid and non-myeloid cancer cell. 
     
     
         31 . The use according to any of  claims 27  to  30 , wherein the cell-death preventing protein is cFLIP and/or Bcl-2 and/or Bcl-x L . 
     
     
         32 . The use according to any of  claims 27  to  31 , wherein the cytokine antagonist is an antibody that binds to IL-4 and/or IL 10 and/or IL-13. 
     
     
         33 . The use according to any of  claims 13  to  23 , wherein the cancer is a non-lymphoid and non-myeloid cancer. 
     
     
         34 . The use according to  claim 33 , wherein the cytokine is IL-4 and/or IL-10 and/or IL-13. 
     
     
         35 . The use according to  claim 33  or  34 , wherein the cytokine is autocrinely produced by the non-lymphoid and non-myeloid cancer. 
     
     
         36 . The use according to any of  claims 33  to  35 , wherein the cancer is selected from the group consisting of thyroid carcinoma, breast carcinoma, lung carcinoma, prostate carcinoma, bladder carcinoma and colon carcinoma. 
     
     
         37 . The use according to  claim 36 , wherein the cancer is thyroid carcinoma. 
     
     
         38 . A medicament for the treatment of a non-lymphoid and/or non-myeloid cancer, which autocrinely produce a cytokine, comprising a cytokine antagonist as defined in any of  claims 6  to  8 , optionally in combination with at least one active compound, and a pharmaceutically acceptable carrier. 
     
     
         39 . A method for the down-regulation of an anti-apoptotic protein in a non-lymphoid and/or non-myeolid cancer target cell which autocrinely produces a cytokine, preferably an interleukin, the method comprising contacting the target cell or the sample with a cytokine antagonist as defined in any of  claims 6  to  8 . 
     
     
         40 . The method according to  claim 39 , wherein the cytokine antagonist is delivered to the proximity of or into the target cell. 
     
     
         41 . The method according to  claim 40 , wherein the cytokine antagonist is delivered via a retroviral vector.