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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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Related in: MedlinePlus

Ring opening and closingof M1dG in duplex DNA. When a dC residue is placed oppositeM1dG, it opens quantitatively. No ring-opening is observedwith dT is placed opposite M1dG.
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fig9: Ring opening and closingof M1dG in duplex DNA. When a dC residue is placed oppositeM1dG, it opens quantitatively. No ring-opening is observedwith dT is placed opposite M1dG.

Mentions: Part of the reason for the “low” mutagenicityof M1dG was revealed through studies of its conformationin duplex oligonucleotides.47 When single-strandedoligos containing M1dG are hybridized to complementaryoligonucleotides containing dC opposite the lesion, M1dGrapidly ring-opens to an oxopropenyl derivative (Figure 9). The oxopropenyl group rotates out of the Watson–Crickbase-pairing region and into the minor groove of the duplex.47 Hydrogen bonding between the adducted dG andthe complementary dC is detected by NMR spectroscopy.48 When the duplex is thermally melted, the oxopropenyl grouprapidly cyclizes to the pyrimidopurinone. Both the initial ring-openingand the subsequent ring-closing are catalyzed by DNA. This representsthe first discovery of a DNA-catalyzed transformation of one DNA adductinto another. Interestingly, when single-stranded oligonucleotidescontaining M1dG are hybridized to complementary strandscontaining a dT opposite the lesion, no ring-opening is observed.47 Therefore, duplex vectors containing M1dG opposite dC or dT residues were constructed and replicated inparallel. The ring-closed adduct was five times more mutagenic thanthe ring-opened adduct.45 This probablyrepresents an underestimate of the true differential in mutagenicpotency because the position of the equilibrium between M1dG and OPdG in vivo cannot be determined. Nevertheless, in vitroexperiments in which adducted template-primers containing either M1dG or OPdG were replicated by model DNA polymerases confirmedthe greater ability of the ring-closed adduct to block replicationand induce mutations.48


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

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

Ring opening and closingof M1dG in duplex DNA. When a dC residue is placed oppositeM1dG, it opens quantitatively. No ring-opening is observedwith dT is placed opposite M1dG.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig9: Ring opening and closingof M1dG in duplex DNA. When a dC residue is placed oppositeM1dG, it opens quantitatively. No ring-opening is observedwith dT is placed opposite M1dG.
Mentions: Part of the reason for the “low” mutagenicityof M1dG was revealed through studies of its conformationin duplex oligonucleotides.47 When single-strandedoligos containing M1dG are hybridized to complementaryoligonucleotides containing dC opposite the lesion, M1dGrapidly ring-opens to an oxopropenyl derivative (Figure 9). The oxopropenyl group rotates out of the Watson–Crickbase-pairing region and into the minor groove of the duplex.47 Hydrogen bonding between the adducted dG andthe complementary dC is detected by NMR spectroscopy.48 When the duplex is thermally melted, the oxopropenyl grouprapidly cyclizes to the pyrimidopurinone. Both the initial ring-openingand the subsequent ring-closing are catalyzed by DNA. This representsthe first discovery of a DNA-catalyzed transformation of one DNA adductinto another. Interestingly, when single-stranded oligonucleotidescontaining M1dG are hybridized to complementary strandscontaining a dT opposite the lesion, no ring-opening is observed.47 Therefore, duplex vectors containing M1dG opposite dC or dT residues were constructed and replicated inparallel. The ring-closed adduct was five times more mutagenic thanthe ring-opened adduct.45 This probablyrepresents an underestimate of the true differential in mutagenicpotency because the position of the equilibrium between M1dG and OPdG in vivo cannot be determined. Nevertheless, in vitroexperiments in which adducted template-primers containing either M1dG or OPdG were replicated by model DNA polymerases confirmedthe greater ability of the ring-closed adduct to block replicationand induce mutations.48

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