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Inflammation and cancer: chemical approaches to mechanisms, imaging, and treatment.

Marnett LJ - J. Org. Chem. (2012)

Bottom Line: Chronic inflammation contributes to the etiology of multiple diseases, especially those associated with aging, such as cancer and cardiovascular disease.The current perspective summarizes our research on unsaturated fatty acid oxidation in the context of inflammation and cancer.In addition to understanding the consequences of DNA and protein modification by lipid electrophiles, our research has focused on the development of molecularly targeted agents to image and treat cancer.

View Article: PubMed Central - PubMed

Affiliation: A.B. Hancock Jr. Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA. larry.marnett@vanderbilt.edu

ABSTRACT
The inflammatory response represents a first line of defense against invading pathogens and is important to human health. Chronic inflammation contributes to the etiology of multiple diseases, especially those associated with aging, such as cancer and cardiovascular disease. The chemistry of the inflammatory response is complex and involves the generation of highly reactive oxidants and electrophiles designed to kill the pathogen as well as the release of small molecule and protein mediators of intercellular signaling, chemotaxis, vasoconstriction, and wound-healing. Oxidation of unsaturated fatty acids--either nonenzymatic or enzymatic--contributes to the inflammatory response and associated cellular pathologies. The current perspective summarizes our research on unsaturated fatty acid oxidation in the context of inflammation and cancer. In addition to understanding the consequences of DNA and protein modification by lipid electrophiles, our research has focused on the development of molecularly targeted agents to image and treat cancer.

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FluorocoxibsA and B.
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fig21: FluorocoxibsA and B.

Mentions: Our laboratory described several years ago thatamides and esters of certain carboxylic acid-containing NSAIDs exhibitCOX-2 selectivity.105 This provided thebasis for our design strategy for the construction of COX-2-targetedimaging agents. An NSAID core is tethered to a fluorophore to generatean optical imaging agent that will accumulate in COX-2 expressingcells and tissue. To test our strategy, we evaluated a number of NSAIDcores, a variety of tethers, and multiple different fluorophores.Each compound was evaluated for COX-2 selectivity against purifiedCOX-1 and COX-2, for potency in intact cells, and for the abilityto image COX-2 in intact cells. Candidates that survived this gauntletwere then evaluated in mouse models of inflammation and cancer fortheir ability to accumulate in tissues expressing high levels of COX-2.Some 250 compounds were made and evaluated; most of them did not inhibitCOX-2 or they did not penetrate the cell membrane. However, two compoundswere quite effective in both in vitro and in vivo experiments.106 These compounds contained indomethacin as theNSAID core tethered through a butylenediamine linker to the fluorophorecarboxy-X-rhodamine (Figure 21).


Inflammation and cancer: chemical approaches to mechanisms, imaging, and treatment.

Marnett LJ - J. Org. Chem. (2012)

FluorocoxibsA and B.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3375764&req=5

fig21: FluorocoxibsA and B.
Mentions: Our laboratory described several years ago thatamides and esters of certain carboxylic acid-containing NSAIDs exhibitCOX-2 selectivity.105 This provided thebasis for our design strategy for the construction of COX-2-targetedimaging agents. An NSAID core is tethered to a fluorophore to generatean optical imaging agent that will accumulate in COX-2 expressingcells and tissue. To test our strategy, we evaluated a number of NSAIDcores, a variety of tethers, and multiple different fluorophores.Each compound was evaluated for COX-2 selectivity against purifiedCOX-1 and COX-2, for potency in intact cells, and for the abilityto image COX-2 in intact cells. Candidates that survived this gauntletwere then evaluated in mouse models of inflammation and cancer fortheir ability to accumulate in tissues expressing high levels of COX-2.Some 250 compounds were made and evaluated; most of them did not inhibitCOX-2 or they did not penetrate the cell membrane. However, two compoundswere quite effective in both in vitro and in vivo experiments.106 These compounds contained indomethacin as theNSAID core tethered through a butylenediamine linker to the fluorophorecarboxy-X-rhodamine (Figure 21).

Bottom Line: Chronic inflammation contributes to the etiology of multiple diseases, especially those associated with aging, such as cancer and cardiovascular disease.The current perspective summarizes our research on unsaturated fatty acid oxidation in the context of inflammation and cancer.In addition to understanding the consequences of DNA and protein modification by lipid electrophiles, our research has focused on the development of molecularly targeted agents to image and treat cancer.

View Article: PubMed Central - PubMed

Affiliation: A.B. Hancock Jr. Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA. larry.marnett@vanderbilt.edu

ABSTRACT
The inflammatory response represents a first line of defense against invading pathogens and is important to human health. Chronic inflammation contributes to the etiology of multiple diseases, especially those associated with aging, such as cancer and cardiovascular disease. The chemistry of the inflammatory response is complex and involves the generation of highly reactive oxidants and electrophiles designed to kill the pathogen as well as the release of small molecule and protein mediators of intercellular signaling, chemotaxis, vasoconstriction, and wound-healing. Oxidation of unsaturated fatty acids--either nonenzymatic or enzymatic--contributes to the inflammatory response and associated cellular pathologies. The current perspective summarizes our research on unsaturated fatty acid oxidation in the context of inflammation and cancer. In addition to understanding the consequences of DNA and protein modification by lipid electrophiles, our research has focused on the development of molecularly targeted agents to image and treat cancer.

Show MeSH
Related in: MedlinePlus