Materials and methods for treatment of inflammatory and cell proliferation disorders

Abstract

The present invention pertains to methods for treatment of inflammatory and cell proliferation disorders, such as cancer, by administering an agent that reduces atrial natriuretic peptide receptor-A (NPR-A) activity. In one aspect, the invention concerns a method for treatment of inflammatory and cell proliferation disorders, such as cancer, by administration of an effective amount of natriuretic hormone peptide (NP), or a polynucleotide encoding NP and an operably-linked promoter sequence. In another aspect, the present invention includes a pharmaceutical composition comprising an agent that reduces the activity of atrial natriuretic peptide receptor-A (NPR-A), and an anti-cancer agent. In another aspect, the present invention further concerns a method for identifying an agent useful for treating an inflammatory or cell proliferation disorder, comprising determining whether the agent reduces the activity of atrial natriuretic peptide receptor-A (NPR-A).

1 . A method of treating or reducing the onset of an inflammatory or cell proliferation disorder, comprising administering a natriuretic hormone peptide (NP), or a polynucleotide encoding NP and an operably-linked promoter sequence, to a patient in need thereof.  
     
     
         2 . The method of  claim 1 , wherein said administering comprises administering the NP to the patient, and wherein the NP comprises an amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:5 and SEQ ID NO:6, or a biologically active fragment or homolog of any of the foregoing.  
     
     
         3 . The method of  claim 1 , wherein said administering comprises administering the polynucleotide encoding NP to the patient, and wherein the NP comprises an amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, or a biologically active fragment or homolog of any of the foregoing.  
     
     
         4 . The method of  claim 1 , wherein said administering is by a route selected from the group consisting of oral, intramuscular, parenteral, intravenous, and intranasal.  
     
     
         5 . The method of  claim 1 , wherein the NP or the polynucleotide is administered with a pharmaceutically acceptable carrier.  
     
     
         6 . The method of  claim 1 , wherein said administering comprises administering the polynucleotide to the patient, and wherein the polynucleotide is contained within an expression vector.  
     
     
         7 . The method of  claim 6 , wherein the expression vector is a DNA plasmid or virus.  
     
     
         8 . The method of  claim 1 , wherein said administering comprises administering the polynucleotide to the patient, and wherein the nucleic acid sequence is administered with chitosan.  
     
     
         9 . The method of  claim 1 , wherein the inflammatory or proliferation disorder is cancer.  
     
     
         10 . The method of  claim 1 , wherein the patient is suffering from one or more tumors, and wherein the NP causes regression of one or more of the tumors in the patient.  
     
     
         11 . The method of  claim 1 , wherein the NP reduces tumor growth and metastasis in the patient.  
     
     
         12 . The method of  claim 1 , wherein the patient is suffering from the inflammatory or cell proliferation disorder.  
     
     
         13 . The method of  claim 1 , wherein the patient is human.  
     
     
         14 . A method for reducing the activity of atrial natriuretic peptide receptor-A (NPR-A) in cells in vitro or in vivo, comprising administering an effective amount of an agent that reduces NPR-A activity to the cells.  
     
     
         15 . The method of  claim 14 , wherein the agent is selected from the group consisting of a polypeptide, polynucleotide, and small molecule.  
     
     
         16 . The method of  claim 14 , wherein the agent comprises a natriuretic hormone peptide (NP), or a polynucleotide encoding NP and an operably-linked promoter sequence.  
     
     
         17 . A pharmaceutical composition comprising an agent that reduces the activity of atrial natriuretic peptide receptor-A (NPR-A), and an anti-cancer agent.  
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein said anti-cancer agent comprises at least one agent selected from the group consisting of a chemotherapeutic agent, a matrix metalloproteinase (MMP)-inhibitor, an angiogenesis inhibitor, a Bcl-2 antisense oligonucleotide, a PSA based vaccine, a PDGF receptor inhibitor, a microtubule stabilizer, and a pro-apoptotic agent.  
     
     
         19 . The pharmaceutical composition of  claim 17 , wherein the agent comprises a natriuretic hormone peptide (NP), or a polynucleotide encoding NP and an operably-linked promoter sequence.  
     
     
         20 . A method for identifying an agent useful for treating an inflammatory or cell proliferation disorder, comprising determining whether the agent reduces the activity of atrial natriuretic peptide receptor-A (NPR-A).  
     
     
         21 . The method of  claim 20 , wherein said determining comprises providing a host cell that produces NPR-A; contacting the host cell with the candidate agent in vitro or in vivo; and determining whether the candidate agent reduces intracellular cGMP.