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Guanylate cyclase receptor agonists for the treatment of tissue inflammation and carcinogenesis

A technology of guanylate cyclase and receptor antagonists, which is applied in the field of guanylate cyclase receptor antagonists, and can solve the problems of decreased production of uroguanylin and guanylin

Inactive Publication Date: 2004-12-01
SYNERGY PHARMA
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Problems solved by technology

[0007] Other papers also reported that the production of uroguanylin and guanylin were significantly reduced in colonic polyps and tumor tissues in the early stage of canceration (14-17)

Method used

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Embodiment

[0140] Materials and Methods

[0141] Cell culture: Human T84 colon tumor cells were obtained from the American Type Culture Collection (ATCC) at passage 52. Cells were grown in a 1:1 mixture of Ham's F-12 medium and Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum, 100 units per milliliter of penicillin, and 100 micrograms per milliliter of streptomycin. Replace with fresh medium every two days, and split the bottles when the confluence rate is about 80%.

[0142] T84 Cell Based Assay for Determining Intracellular cGMP Levels: Phthaloids were custom synthesized by Multiple Peptide Systems, San Diego, CA and Princeton Biomolecules Langhorne, PA. The biological activity of the synthetic peptides was determined according to previous reports (15). The brief steps are as follows. The confluent monolayer cells in the 24-well culture plate were washed twice with 250 microliters of DMEM containing 50 mM HEPES (pH7.4), and washed with 250 microlit...

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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.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of the following U.S. provisional applications: 60 / 279,438 filed March 29, 2001; 60 / 279,437 filed March 29, 2001; 60 / 300,850 filed June 27, 2001; July 2001 60 / 303,806 filed on 10; 60 / 307,358 filed on 25 July 2001; 60 / 348,646 filed on 17 January 2002. field of invention [0003] The present invention relates to the therapeutic use of guanylate cyclase receptor antagonists as a means of increasing intracellular cGMP production. The antagonists can be used alone or in combination with inhibitors of cGMP-specific phosphodiesterases to prevent or treat cancerous, precancerous and metastatic tumor growth, especially in the gastrointestinal tract and lung. Among other things, the antagonist could be used to treat inflammatory conditions such as ulcerative colitis and asthma. Background of the invention [0004] Uroguanylin, guanylin, and bacterial ST peptide are structurally related pepti...

Claims

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Application Information

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IPC IPC(8): A61K9/08A61K9/14A61K9/48A61K9/72A61K38/00A61K38/10A61K38/12A61K45/00A61K45/06A61K47/48A61P1/00A61P1/04A61P1/16A61P1/18A61P11/00A61P11/06A61P13/08A61P13/10A61P13/12A61P15/00A61P29/00A61P35/00A61P35/02A61P35/04A61P43/00C07K7/00C07K7/08C07K7/64
CPCC07K7/08C07K2299/00A61K47/48215A61K38/00A61K45/06A61K38/12A61K47/60A61P29/00A61K38/10Y02A50/30C07K7/50C07K7/64
Inventor K·沙鲁布海G·尼克夫维茨G·S·雅克布
Owner SYNERGY PHARMA
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