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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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Oligomerization of MDAand the formation of DNA adducts.
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fig4: Oligomerization of MDAand the formation of DNA adducts.

Mentions: Our initial efforts in this area focusedon the identification of chemical adducts formed by the reaction ofMDA with DNA. This turned out to be much more complicated than initiallyanticipated because MDA, or more correctly β-hydroxyacrolein(Figure 4), is as good a nucleophile as itis an electrophile and undergoes oligomerization under conditionsof its chemical generation. Thus, adducts to deoxyguanosine, deoxyadenosine,and deoxycytidine were formed by reaction of MDA as well as by reactionwith dimers and trimers of MDA (Figure 4).36−40 The structures of these interesting adducts suggested that theyshould block DNA replication or induce mutations by virtue of thefact that they either completely disrupted or attached sizable organicfunctionality to exocyclic amino groups in the Watson–Crickbase-pairing region of the adducted base.


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

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

Oligomerization of MDAand the formation of DNA adducts.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: Oligomerization of MDAand the formation of DNA adducts.
Mentions: Our initial efforts in this area focusedon the identification of chemical adducts formed by the reaction ofMDA with DNA. This turned out to be much more complicated than initiallyanticipated because MDA, or more correctly β-hydroxyacrolein(Figure 4), is as good a nucleophile as itis an electrophile and undergoes oligomerization under conditionsof its chemical generation. Thus, adducts to deoxyguanosine, deoxyadenosine,and deoxycytidine were formed by reaction of MDA as well as by reactionwith dimers and trimers of MDA (Figure 4).36−40 The structures of these interesting adducts suggested that theyshould block DNA replication or induce mutations by virtue of thefact that they either completely disrupted or attached sizable organicfunctionality to exocyclic amino groups in the Watson–Crickbase-pairing region of the adducted base.

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