Materials and methods for treatment of inflammatory and cell proliferation disorders

Inactive Publication Date: 2005-12-08
UNIV OF SOUTH FLORIDA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0010] In one embodiment, the method of the present invention comprises administering a therapeutically effective amount of an agent that reduces NPR-A activity. In another embodiment, the method of the present invention comprises administering a therapeutically effective amount of an N-terminal natriuretic peptide (referred to herein as NP or NP peptide), or a polynucleotide encoding NP and an operably-linked promoter sequence, to a patient in need of such treatment. As used herein, NP refers to peptides derived from atria

Problems solved by technology

Increased IL-6 in lung cancer patients enhances the acute phase response, and is correlated w

Method used

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  • Materials and methods for treatment of inflammatory and cell proliferation disorders
  • Materials and methods for treatment of inflammatory and cell proliferation disorders
  • Materials and methods for treatment of inflammatory and cell proliferation disorders

Examples

Experimental program
Comparison scheme
Effect test

Example

EXAMPLE 1

pNP 73-102 Inhibits NPRA Expression

[0167] The structures of ANP and ANP like molecules with their ring-structure and receptors associated with it are well characterized. However, the N-terminal peptides do not have this structure. Neither KP nor NP73-102 was shown to bind ANP receptor NPRA (Mohapatra et al., J Allergy Clin Immunol, 2004, 114:520-526). The receptors for NP-73-102 are not known.

[0168] The highest expression of the ANP and ANP receptors is found in neonatal thymus. To test whether the peptide NP73-102 inhibits in vivo the ANP cascade, pregnant (12 days) mice were injected i.p. with pVAX (vector), or pNP73-102. After 1 day, mice were sacrificed and thymi removed from embryo, were homogenized. Cells were centrifuged and erythrocytes lysed by treating the suspension with ACK buffer. Cells were incubated with anti-NPRA or anti-NPRC antibodies for 1 hour, washed and incubated with PE-conjugated 20 Ab. Levels of NPR's were determined by flow cytometry. The result...

Example

EXAMPLE 2

NPRA Deficiency Decreases Pulmonary Inflammation

[0169] Development and chronicity of cancers has been attributed to the chronic inflammation in the affected organs. ANP was reported to have anti-inflammatory activity, although signaling through NPRA is known to cause a number of different biological activity including cell proliferation, immune activation, inflammation and apoptosis. To determine the role of NPRA signaling in the lung inflammation, groups (n=3) of wild type DBA / 2 (wt) and NPR-C (ko) deficient mice and wild type C57 / BL6 (wt) and NPR-A (ko) were sensitized with ovalbumin (20 mg / mouse) and after 2 weeks challenged i.n. with ovalbumin (20 mg / mouse). One day later, mice were sacrificed and lung sections were stained with H & E to examine inflammation. As shown in FIGS. 2A-2D, there was no significant difference in pulmonary inflammation between the wild-type and NPRC deficient mice. In sharp contrast, a comparison between wild-type C57BL6 and NPRA deficient mi...

Example

EXAMPLE 3

A549 Cells Transfected with pNP73-102 Show a Significantly Higher Level of Apoptosis Compared Control and pANP or pVAX

[0170] To determine the effect of overexpression of NP73-102 on proliferation of A549 lung epithelial cells, cells were transfected with either pNP73-102 or vector, pVAX. Cell cycle analysis was performed using propidium iodide (PI) staining and flow cytometry 48 h after transfection. No significant difference was observed between control and pNP73-102-transfected cells in S1, Go-G1 and G2-M stages of cell cycle (data not shown). However, an analysis of apoptosis using flow-cytometry with PI and annexin V, showed that cells transfected with pNP73-102 exhibited significantly higher apoptosis compared to cells transfected with either the control plasmid or a plasmid encoding ANP (FIGS. 3A-3C). This result was confirmed by (i) staining by TUNEL of A549 cells cultured in 8-chamber slide following a 48-hour transfection with either pANP or pNP73-102 (not shown)...

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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).

Description

CROSS-REFERENCE TO RELATED APPLICATION [0001] The present application claims the benefit of U.S. Provisional Application Ser. No. 60 / 521,072, filed Feb. 17, 2004, which is hereby incorporated by reference herein in its entirety, including any figures, tables, nucleic acid sequences, amino acid sequences, or drawings.BACKGROUND OF THE INVENTION [0002] The vast majority of cancers of the lung, breast and colon are adenocarcinomas, which arise from pre-existing adenomatous polyps that develop in the normal colonic mucosa. This adenoma-carcinoma sequence is a well-characterized clinical and histopathologic series of events with which discrete molecular genetic alterations have been associated. Lung tumor development and metastasis are complex processes that include transformation, proliferation, resistance to apoptosis, neovascularization, and metastatic spread. A number of gene products have been identified that play critical roles in these processes. It has been suggested that the dev...

Claims

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Application Information

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IPC IPC(8): A61K38/22A61K48/00
CPCA61K38/2242A61K48/0008A61K48/005G01N2500/04G01N2500/10A61P35/00
Inventor MOHAPATRA, SHYAM
Owner UNIV OF SOUTH FLORIDA
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