Colon cancer chemoprevention by a novel NO chimera that shows anti-inflammatory and antiproliferative activity in vitro and in vivo.

Colon cancer chemoprevention by a novel NO chimera that shows anti-inflammatory and antiproliferative activity in vitro and in vivo. Research Abstract Details 

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Colon cancer chemoprevention by a novel NO chimera that shows anti-inflammatory and antiproliferative activity in vitro and in vivo. Abstract Text:

Ghenet K Hagos,Robert E Carroll,Tatiana Kouznetsova,Qian Li,Violeta Toader,Patricia A Fernandez,Steven M Swanson,Gregory R J Thatcher,

Chemopreventive agents in colorectal cancer possess either antiproliferative or anti-inflammatory actions. Nonsteroidal anti-inflammatory drugs (NSAID) and cyclooxygenase-2 inhibitors have shown promise, but are compromised by side effects. Nitric oxide donor NSAIDs are organic nitrates conjugated via a labile linker to an NSAID, originally designed for use in pain relief, that have shown efficacy in colorectal cancer chemoprevention. The NO chimera, GT-094, is a novel nitrate containing an NSAID and disulfide pharmacophores, a lead compound for the design of agents specifically for colorectal cancer. GT-094 is the first nitrate reported to reduce aberrant crypt foci (by 45%) when administered after carcinogen in the standard azoxymethane rat model of colorectal cancer. Analysis of proximal and distal colon tissue from 8- and 28-week rat/azoxymethane studies showed that GT-094 treatment reduced colon crypt proliferation by 30% to 69%, reduced inducible NO synthase (iNOS) levels by 33% to 67%, reduced poly(ADP-ribose)polymerase-1 expression and cleavage 2- to 4-fold, and elevated levels of p27 in the distal colon 3-fold. Studies in cancer cell cultures recapitulated actions of GT-094: antiproliferative activity and transient G(2)-M phase cell cycle block were measured in Caco-2 cells; apoptotic activity was examined but not observed; anti-inflammatory activity was seen in the inhibition of up-regulation of iNOS and endogenous NO production in lipopolysaccharide (LPS)-induced RAW 264.7 cells. In summary, antiproliferative, anti-inflammatory, and cytoprotective activity observed in vivo and in vitro support GT-094 as a lead compound for the design of NO chimeras for colorectal cancer chemoprevention.

Colon cancer chemoprevention by a novel NO chimera that shows anti-inflammatory and antiproliferative activity in vitro and in vivo. Publishing Authors By Initials

GK Hagos,RE Carroll,T Kouznetsova,Q Li,V Toader,PA Fernandez,SM Swanson,GR Thatcher,

For similar animals: animal population groups: animals, inbred strains: rats, inbred strains: rats, inbred f344 research abstracts see: animals: animal population groups: animals, inbred strains: rats, inbred strains: rats, inbred f344 research

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Colon cancer chemoprevention by a novel NO chimera that shows anti-inflammatory and antiproliferative activity in vitro and in vivo. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Molecular cancer therapeutics

VOLUME: 6

Page Numbers: 2230-9

Journal Abbreviation: Mol. Cancer Ther.

ISSN: 1535-7163

DAY: 3

MONTH: Aug

YEAR: 2007

Colon cancer chemoprevention by a novel NO chimera that shows anti-inflammatory and antiproliferative activity in vitro and in vivo. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 101132535

Colon cancer chemoprevention by a novel NO chimera that shows anti-inflammatory and antiproliferative activity in vitro and in vivo. Keywords Mesh Terms:

KEYWORDS: Rats, Inbred F344

MESH TERMS: pathology

Chemical & Substance for Abstract: Colon cancer chemoprevention by a novel NO chimera that shows anti-inflammatory and antiproliferative activity in vitro and in vivo. Information

Substance Name: Poly(ADP-ribose) Polymerases

Registry Number: EC 2.4.2.30

Grant and Affiliation Information for Colon cancer chemoprevention by a novel NO chimera that shows anti-inflammatory and antiproliferative activity in vitro and in vivo.

AFFILIATION: Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 S Wood Street, Chicago, IL 60612, USA.

Country: United States

AGENCY: United States NCI

GRANT: CA-80360

ACRONYM: CA

MEDLINETA: Mol Cancer Ther

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