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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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Comparison of fluorocoxibB uptake with that of LM4752. The same protocol was followed as describedin Figure 23. Reproduced with permission fromref (106). 2010. AmericanAssociation for Cancer Research.
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fig24: Comparison of fluorocoxibB uptake with that of LM4752. The same protocol was followed as describedin Figure 23. Reproduced with permission fromref (106). 2010. AmericanAssociation for Cancer Research.

Mentions: Indeed, this is one of the attractive featuresof the footpad model of inflammation; every animal serves as its owncontrol. Parallel experiments using animals in which COX-2 had beengenetically deleted (i.e., COX-2 knockouts) revealed no selectiveaccumulation in the inflamed compared to the noninflamed paw, indicatingthat the uptake in the wild-type animals was dependent upon the presenceof COX-2 in the tissue. This was confirmed by pretreating wild-typeanimals with either the nonselective NSAID, indomethacin, or the selectiveCOX-2 inhibitor, celecoxib, prior to fluorocoxib administration. Eitherinhibitor prevented accumulation of fluorocoxib in the inflamed lesion.A particularly useful control compound is an analog of fluorocoxibB in which the four-carbon tether is shortened to two carbons. Becauseof the shortened tether, this compound is unable to inhibit COX-2.It contains the same indomethacin core and the same carboxy-X-rhodaminefluorophore but it is not a COX-2 inhibitor, so it is a very usefulnegative control for in vivo experiments. Comparison of the uptakeof fluorocoxib B and the negative control molecule (Figure 24) illustrates that no accumulation in the inflamedlesion is observed following injection of the compound that is unableto bind to COX-2. Thus, genetic and pharmacological experiments validatethe hypothesis that fluorocoxib A and B accumulate in inflamed tissuebecause of the presence of COX-2 in that tissue.


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

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

Comparison of fluorocoxibB uptake with that of LM4752. The same protocol was followed as describedin Figure 23. Reproduced with permission fromref (106). 2010. AmericanAssociation for Cancer Research.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig24: Comparison of fluorocoxibB uptake with that of LM4752. The same protocol was followed as describedin Figure 23. Reproduced with permission fromref (106). 2010. AmericanAssociation for Cancer Research.
Mentions: Indeed, this is one of the attractive featuresof the footpad model of inflammation; every animal serves as its owncontrol. Parallel experiments using animals in which COX-2 had beengenetically deleted (i.e., COX-2 knockouts) revealed no selectiveaccumulation in the inflamed compared to the noninflamed paw, indicatingthat the uptake in the wild-type animals was dependent upon the presenceof COX-2 in the tissue. This was confirmed by pretreating wild-typeanimals with either the nonselective NSAID, indomethacin, or the selectiveCOX-2 inhibitor, celecoxib, prior to fluorocoxib administration. Eitherinhibitor prevented accumulation of fluorocoxib in the inflamed lesion.A particularly useful control compound is an analog of fluorocoxibB in which the four-carbon tether is shortened to two carbons. Becauseof the shortened tether, this compound is unable to inhibit COX-2.It contains the same indomethacin core and the same carboxy-X-rhodaminefluorophore but it is not a COX-2 inhibitor, so it is a very usefulnegative control for in vivo experiments. Comparison of the uptakeof fluorocoxib B and the negative control molecule (Figure 24) illustrates that no accumulation in the inflamedlesion is observed following injection of the compound that is unableto bind to COX-2. Thus, genetic and pharmacological experiments validatethe hypothesis that fluorocoxib A and B accumulate in inflamed tissuebecause of the presence of COX-2 in that tissue.

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