Inhibitors of phospholipase A2

Abstract

The invention relates to methods for identifying prostatic intraepithelial neoplasia, methods for determining metastatic potential of tumors, and to methods and compositions for inhibiting or preventing metastasis of cancers. In one aspect, the invention provides a method to determine metastatic potential of tumors, particularly prostatic tumors. In another aspect, the invention provides a method of identifying prostate cancer associated conditions, particularly prostatic intraepithelial neoplasia. In these regards, the invention relates to determining protein or mRNA of effectors of arachidonic acid release, particularly uteroglobin protein or mRNA, to identify intermediate conditions such as PIN or to gauge metastatic potential of prostatic tumors. The invention also relates to methods and compositions that prevent or inhibit metastasis of cancers. In this regard, the invention particularly relates to methods and compositions that inhibit arachidonic acid, those that inhibit phospholipase A 2 . More particularly in this regard, the invention relates to uteroglobin or muteins, peptide analogs or mimetics of uteroglobin and lipocortins or muteins, peptide analogs, or mimetics of lipocortins that inhibit metastasis. Especially it relates to methods and compositions in which uteroglobins, particularly human uteroglobins, inhibit or prevent metastasis of cancer, particularly prostatic cancer.

What is claimed is:  
     
         1 . A method for preventing or inhibiting metastasis of a cancer of epithelial cell origin, comprising the step of administering to an organism suffering from a cancer of epithelial cell origin a compound that inhibits arachidonic acid release by cells of said cancer, by a route and in an amount effective to inhibit or prevent metastasis of said tumor.  
     
     
         2 . A method according to  claim 1 , wherein said compound is an inhibitor of phospholipase A 2  or cyclooxygenase.  
     
     
         3 . A method according to  claim 1 , wherein said compound is mepacrine or indomethacin.  
     
     
         4 . A method according to  claim 1 , wherein said compound is a lipocortin, a mutein of a lipocortin, a peptide analog of a lipocortin, or a mimetic of lipocortin.  
     
     
         5 . A method according to  claim 1 , wherein said compound is a uteroglobin, a mutein of a uteroglobin, a peptide analog of a uteroglobin or a mimetic of uteroglobin.  
     
     
         6 . A method according to  claim 1 , wherein said compound is a uteroglobin.  
     
     
         7 . A method according to  claim 6 , wherein said compound is human uteroglobin.  
     
     
         8 . A method according to  claim 1 , wherein said tumor is a cancer of the prostate gland in a human patient.  
     
     
         9 . A method according to  claim 2 , wherein said tumor is a cancer of the prostate gland in a human patient.  
     
     
         10 . A method according to  claim 5 , wherein said tumor is a cancer of the prostate gland in a human patient.  
     
     
         11 . A method according to  claim 6 , wherein said tumor is a cancer of the prostate gland in a human patient.  
     
     
         12 . A method according to  claim 7 , wherein said tumor is a cancer of the prostate gland in a human patient.  
     
     
         13 . A method according to  claim 1 , wherein said method is used in conjunction with another treatment.  
     
     
         14 . A method according to  claim 13 , wherein said treatment is surgical intervention, radiation therapy, hormonal therapy, immunotherapy, chemotherapy, cryotherapy or gene therapy.  
     
     
         15 . A pharmaceutical composition for inhibiting or preventing metastasis of a cancer of epithelial cell origin, comprising: (i) a compound that inhibits arachidonic acid release by cells of a tumor of epithelial cell origin effective to prevent or inhibit metastasis of said tumor in an organism and (ii) a carrier for effective therapeutic administration of said compound to said organism.  
     
     
         16 . A composition according to  claim 15 , wherein said compound is an inhibitor of phospholipase A 2  or cyclooxygenase.  
     
     
         17 . A composition according to  claim 15 , wherein said compound is mepacrine or indomethacin.  
     
     
         18 . A composition according to  claim 17 , wherein said compound is a lipocortin, a mutein of a lipocortin, a peptide analog of a lipocortin or a mimetic of lipocortin.  
     
     
         19 . A composition according to  claim 15 , wherein said compound is a uteroglobin, a mutein of a uteroglobin a peptide analog of a uteroglobin or a mimetic of uteroglobin.  
     
     
         20 . A composition according to  claim 19 , wherein said compound is a uteroglobin.  
     
     
         21 . A composition according to  claim 20 , wherein said compound is human uteroglobin.  
     
     
         22 . A method for determining metastatic potential of a tumor of epithelial cell origin, comprising the steps of: 
 (A) determining an effector of arachidonic acid release in cells in a biopsy sample of a tumor;    (B) comparing effector in tumor cells in said biopsy sample with effector in fiduciary cells, and    (C) determining metastatic potential, 
 wherein effector in said tumor cells characteristic of normal fiduciary cells or characteristic of fiduciary cells of benign tumors indicates low metastatic potential and effector in said tumor cells characteristic of fiduciary cells of metastatic tumors indicates high metastatic potential.  
   
     
     
         23 . A method for determining metastatic potential of a tumor, according to  claim 22 , wherein said effector is an inhibitor of PLA 2  or cyclooxygenase.  
     
     
         24 . A method for determining metastatic potential of a tumor according to  claim 23 , wherein said inhibitor is uteroglobin.  
     
     
         25 . A method according to  claim 22 , wherein said effector is determined assaying a protein in cells of said tumor.  
     
     
         26 . A method for determining metastatic potential of a tumor, according to  claim 25 , wherein said effector is an inhibitor of PLA 2 .  
     
     
         27 . A method for determining metastatic potential of a tumor according to  claim 26 , wherein said inhibitor is uteroglobin.  
     
     
         28 . A method according to  claim 25 , wherein said protein is determined by immunocytochemistry.  
     
     
         29 . A method for determining metastatic potential of a tumor according to  claim 28 , wherein said effector is an inhibitor of PLA 2 .  
     
     
         30 . A method for determining metastatic potential of a tumor according to  claim 29 , wherein said inhibitor is uteroglobin.  
     
     
         31 . A method according to  claim 22 , wherein said effector is determined by assaying an mRNA in cells of said tumor.  
     
     
         32 . A method for determining metastatic potential of a tumor according to  claim 31 , wherein said effector is an inhibitor of PLA 2 .  
     
     
         33 . A method for determining metastatic potential of a tumor according to  claim 32 , wherein said inhibitor is uteroglobin.  
     
     
         34 . A method according to  claim 31 , wherein said mRNA is determined by in situ hybridization.  
     
     
         35 . A method for determining metastatic potential of a tumor, according to  claim 34 , wherein said effector is an inhibitor of PLA 2 .  
     
     
         36 . A method for determining metastatic potential of a tumor according to  claim 35 , wherein said inhibitor is uteroglobin.  
     
     
         37 . A method according to  claim 32 , wherein an aberrant mRNA is determined.  
     
     
         38 . A method for determining metastatic potential of a tumor according to  claim 37 , wherein said inhibitor is uteroglobin.  
     
     
         39 . A method according to  claim 25 , wherein said tumor is a prostatic adenocarcinoma, and said inhibitor is uteroglobin.  
     
     
         40 . A method according to  claim 31 , wherein said tumor is a prostatic adenocarcinoma, and said inhibitor is uteroglobin.  
     
     
         41 . A kit for determining metastatic potential of a tumor, comprising: 
 (A) a first reagent that binds specifically to an effector of arachidonic acid release in cells in a biopsy sample prepared for determination of said effector, and    (B) a second reagent for detectably labelling said primary binding reagent bound specifically to cells in said biopsy sample, 
 wherein the determination of said effector tumor is diagnostic of the metastatic potential of said tumor.  
   
     
     
         42 . A kit according to  claim 41 , wherein said effector is an inhibitor of PLA 2 .  
     
     
         43 . A kit according to  claim 42 , wherein said inhibitor is uteroglobin.  
     
     
         44 . A kit according to  claim 41 , wherein said first reagent is an antibody.  
     
     
         45 . A kit according to  claim 44 , wherein said effector is an inhibitor of PLA 2 .  
     
     
         46 . A kit according to  claim 45 , wherein said inhibitor is uteroglobin.  
     
     
         47 . A kit according to  claim 41 , wherein said first reagent is a hybridization probe.  
     
     
         48 . A kit according to  claim 47 , wherein said effector is an inhibitor of PLA 2 .  
     
     
         49 . A kit according to  claim 48 , wherein said inhibitor is uteroglobin.  
     
     
         50 . A method for identifying prostatic intraepithelial neoplasia, comprising the steps of: 
 (A) determining an effector of arachidonic acid release in cells in a biopsy sample of tissue;    (B) comparing effector in cells in said biopsy sample with effector in fiduciary cells, and    (C) identifying presence of prostatic intraepithelial neoplasia, wherein a high concentration of effector in said biopsy sample indicates normal tissue or low grade prostatic intraepithelial neoplasia, a low concentration of effector in said biopsy sample indicates high grade prostatic intraepithelial neoplasia, and substantially no concentration of effector in said biopsy sample indicates cancer.    
     
     
         51 . A method for identifying prostatic intraepithelial neoplasia according to  claim 50 , wherein said effector is an inhibitor of PLA 2  or cyclooxygenase.  
     
     
         52 . A method for identifying prostatic intraepithelial neoplasia according to  claim 51 , wherein said inhibitor is uteroglobin.  
     
     
         53 . A method according to  claim 50 , wherein said effector is determined by assaying a protein in cells of said biopsy sample.  
     
     
         54 . A method for identifying prostatic intraepithelial neoplasia according to  claim 53 , wherein said effector is an inhibitor of PLA 2 .  
     
     
         55 . A method for identifying prostatic intraepithelial neoplasia according to  claim 54 , wherein said inhibitor is uteroglobin.  
     
     
         56 . A method according to  claim 53 , wherein said protein is determined by immunocytochemistry.  
     
     
         57 . A method for identifying prostatic intraepithelial neoplasia according to  claim 56 , wherein said effector is an inhibitor of PLA 2 .  
     
     
         58 . A method for identifying prostatic intraepithelial neoplasia according to  claim 57 , wherein said inhibitor is uteroglobin.  
     
     
         59 . A method according to  claim 50 , wherein said effector is determined by assaying an mRNA in cells of said biopsy sample.  
     
     
         60 . A method for identifying prostatic intraepithelial neoplasia according to  claim 59 , wherein said effector is an inhibitor of PLA 2 .  
     
     
         61 . A method for identifying prostatic intraepithelial neoplasia according to  claim 60 , wherein said inhibitor is uteroglobin.  
     
     
         62 . A method according to  claim 59 , wherein said mRNA is determined by in situ hybridization.  
     
     
         63 . A method for identifying prostatic intraepithelial neoplasia according to  claim 62 , wherein said effector is an inhibitor of PLA 2 .  
     
     
         64 . A method for identifying prostatic intraepithelial neoplasia according to  claim 63 , wherein said inhibitor is uteroglobin.  
     
     
         65 . A kit for identifying prostatic intraepithelial neoplasia, which comprises: 
 (A) a first reagent that binds specifically to an effector of arachidonic acid release in cells in a biopsy sample prepared for identification of said effector, and    (B) a second reagent for detectably labelling said primary binding reagent bound specifically to cells in said biopsy sample, 
 wherein the identification of said effector is diagnostic of said prostatic intraepithelial neoplasia.  
   
     
     
         66 . A kit according to  claim 65 , wherein said effector is an inhibitor of PLA 2 .  
     
     
         67 . A kit according to  claim 66 , wherein said inhibitor is uteroglobin.  
     
     
         68 . A kit according to  claim 65 , wherein said first reagent is an antibody.  
     
     
         69 . A kit according to  claim 68 , wherein said effector is an inhibitor of PLA 2 .  
     
     
         70 . A kit according to  claim 69 , wherein said inhibitor is uteroglobin.  
     
     
         71 . A kit according to  claim 65 , wherein said first reagent is a hybridization probe.  
     
     
         72 . A kit according to claim  71 , wherein said effector is an inhibitor of PLA 2 .  
     
     
         73 . A kit according to claim  72 , wherein said inhibitor is uteroglobin.