Guanylate Cyclase Receptor Agonists For The Treatment Of Tissue Inflammation And Carcinogenesis

Abstract

A method of treatment of inflamed, pre-cancerous or cancerous tissue or polyps in a mammalian subject is disclosed. The treatment involves administration of a composition of at least one peptide agonist of a guanylate cyclase receptor and/or other small molecules that enhance intracellular production of cGMP. The at least one peptide agonist of a guanylate cyclase receptor may be administered either alone or in combination with an inhibitor of cGMP-dependent phosphodiesterase. The inhibitor may be a small molecule, peptide, protein or other compound that inhibits the degradation of cGMP. Without requiring a particular mechanism of action, this treatment may restore a healthy balance between proliferation and apoptosis in the subject's population of epithelial cells, and also suppress carcinogenesis. Thus, the method may be used to treat, inter alia, inflammation, including gastrointestinal inflammatory disorders, general organ inflammation and asthma, and carcinogenesis of the lung, gastrointestinal tract, bladder, testis, prostate and pancreas, or polyps.

What is claimed is: 
     
         1 . A peptide consisting essentially of the amino acid sequence of any one of SEQ ID NO:2-SEQ ID NO:21, wherein said peptide is a (4,12; 7,15) bicycle peptide. 
     
     
         2 . The peptide of  claim 1 , wherein said peptide is a (4,12; 7,15) bicycle having the sequence of SEQ ID NO:20. 
     
     
         3 . The peptide of  claim 1 , wherein said peptide consists of the amino acid sequence of any one of SEQ ID NO:2-SEQ ID NO:21. 
     
     
         4 . A method for preventing or treating primary or metastatic cancer or polyps in a patient comprising administering to said patient an effective dosage of a guanylate cyclase receptor agonist having the sequence of any one of SEQ ID NO:2-SEQ ID NO:21. 
     
     
         5 . A method for treating metastatic cancer in a patient comprising administering to said patient an effective dosage of a guanylate cyclase receptor agonist selected from the group consisting of: uroguanylin; guanylin; and  E. coli  ST peptide. 
     
     
         6 . A method for treating primary cancers other than colon cancer in a patient, comprising administering to said patient an effective dosage of a guanylate cyclase receptor agonist selected from the group consisting of: uroguanylin; guanylin; and  E. coli  ST peptide. 
     
     
         7 . The method of  claim 4 , wherein said peptide is a (4,12; 7,15) bicyclic peptide having the sequence of SEQ ID NO:20. 
     
     
         8 . The method of  claim 4 , wherein said primary cancer is a member selected from the group consisting of the breast, colon, rectum, lung, ovary, pancreas, bladder, prostate, kidney or testis. 
     
     
         9 . The method of  claim 4 , further comprising administering to said patient an effective dose of an inhibitor of cGMP-dependent phosphodiesterase either concurrently or sequentially with said guanylate cyclase receptor agonist. 
     
     
         10 . A method of treating a patient for colon cancer or polyps comprising administering to said patient an effective dose of an inhibitor of cGMP-dependent phosphodiesterase either concurrently or sequentially with uroguanylin, guanylin or  E. coli  ST peptide. 
     
     
         11 . The method of  claim 10 , wherein said cGMP-dependent phosphodiesterase inhibitor is selected from the group consisting of sulindac sulfone, zaprinast, and motapizone. 
     
     
         12 . A method for preventing or treating inflammation in a patient comprising administering to said patient an effective dosage of a guanylate cyclase receptor agonist having the sequence of any one of: SEQ ID NO:2-SEQ ID NO:21; uroguanylin; guanylin; or  E. coli  ST peptide. 
     
     
         13 . The method of  claim 12 , wherein said peptide is a (4,12; 7,15) bicyclic peptide having the sequence of SEQ ID NO:20. 
     
     
         14 . The method of  claim 12 , wherein said inflammation is an inflammatory disease selected from the group consisting of: asthma, nephritis, hepatitis, pancreatitis, bronchitis and cystic fibrosis. 
     
     
         15 . The method of  claim 12 , wherein said patient is treated for an inflammatory disorder of the gastrointestinal tract. 
     
     
         16 . The method of  claim 15 , wherein said inflammatory disorder of the gastrointestinal tract is an inflammatory bowel disease selected from the group consisting of: ulcerative colitis and Crohn's disease. 
     
     
         17 . The method of  claim 12 , further comprising administering to said patient an effective dose of an inhibitor of cGMP-dependent phosphodiesterase either concurrently or sequentially with said guanylate cyclase receptor agonist. 
     
     
         18 . The method of  claim 17 , wherein said cGMP-dependent phosphodiesterase is selected from the group consisting of sulindac sulfone, zaprinast, and motapizone. 
     
     
         19 . A method of treating a patient for primary or metastatic cancer, polyps or inflammation comprising administering to said patient:
 a) a guanylate cyclase receptor agonist peptide having the sequence of any one of: SEQ ID NOs:2-21; uroguanylin; guanylin; or  E. coli  ST peptide; and   b) at least one compound selected from the group consisting of: a cGMP-dependent phosphodiesterase inhibitor; an anti-inflammatory agent; an antiviral agent; and an anticancer agent;   wherein said guanylate cyclase receptor agonist and said compound are each administered in a therapeutically effective amount.   
     
     
         20 . A pharmaceutical composition in unit dose form comprising a guanylate cyclase receptor agonist peptide having the sequence of any one of SEQ ID NOs:2-21 present in a therapeutically effective amount. 
     
     
         21 . A pharmaceutical composition in unit dose form comprising:
 a) a guanylate cyclase receptor agonist peptide having the sequence of any one of: SEQ ID NOs:2-21; uroguanylin; guanylin; or  E. coli  ST peptide; and   b) at least one compound selected from the group consisting of: a cGMP-dependent phosphodiesterase inhibitor, an anti-inflammatory agent, an antiviral agent and an anticancer agent;   wherein said guanylate cyclase receptor agonist and said compound are each present in a therapeutically effective amount.   
     
     
         22 . The pharmaceutical composition of  claim 20 , wherein the unit dose form is selected from the group consisting of a tablet, a capsule, a solution and inhalation formulation. 
     
     
         23 . The pharmaceutical composition of  claim 20 , further comprising one or more excipients. 
     
     
         24 . A method of inducing apoptosis in the cells of a subject, comprising administering to said subject an effective amount of agonist peptide having the sequence of any one of SEQ ID NO:2-SEQ ID NO:21. 
     
     
         25 . A method of inducing apoptosis in the cells of a subject, comprising administering to said subject an effective amount of uroguanylin, guanylin or  E. coli  ST peptide for cancers other than colon cancer. 
     
     
         26 . A peptide conjugate comprising polyethylene glycol (PEG) attached to a peptide having the sequence of any of: SEQ ID NO:2-SEQ ID NO:21; uroguanylin; guanylin; or  E. coli  ST peptide. 
     
     
         27 . A method of treating cancer, inflammation or polyps in a patient comprising administering to said patient a therapeutically effective amount of the peptide conjugate of  claim 26 .