Abstract

There is considerable interest in the role of polyunsaturated fatty acid oxygenation in malignant transformation. Release of arachidonic acid from phospholipids is an early response of cells to stimulation by hormones, proteinases, tumor promoters, etc. The liberated fatty acid is a substrate for oxygenases that catalyze the committed step in a casade that generates a wide variety of bioactive lipids. Free radicals and hydroperoxides are intermediates in this process, which provides a mechanism for conversion of extracellular recognition events to intracellular oxidation everts. My laboratory is attempting to elucidate the biochemical mechanisms by which polyunsaturated fatty acid oxygenation contributes to tumor initiation, promotion, and metastasis. The projects outlined in this application represent the major focus of our current efforts. We are conducting experiments to (1) determine the role of free radicals and hydroperoxides in tumor initiation and promotion, (2) define the role of DNA modification in the mutagenic activity of carbonyl compounds, and (3) explore the possibility that modulation of PGH synthase is an effective strategy for development of novel antimetastatic agents. Our approach is to exploit the unique chemical features of each biochemical event to develop novel methodologies that we can use to probe to probe relevant biological models.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA047479-06
Application #
3479685
Study Section
Special Emphasis Panel (SRC (88))
Project Start
1988-05-01
Project End
1994-05-31
Budget Start
1993-06-01
Budget End
1994-05-31
Support Year
6
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
Vanderbilt University Medical Center
Department
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212

  Publications

Niedernhofer, Laura J; Daniels, J Scott; Rouzer, Carol A et al. (2003) Malondialdehyde, a product of lipid peroxidation, is mutagenic in human cells. J Biol Chem 278:31426-33
Moody, John S; Marnett, Lawrence J (2002) Kinetics of inhibition of leukocyte 12-lipoxygenase by the isoform-specific inhibitor 4-(2-oxapentadeca-4-yne)phenylpropanoic acid. Biochemistry 41:10297-303
Kalgutkar, Amit S; Rowlinson, Scott W; Crews, Brenda C et al. (2002) Amide derivatives of meclofenamic acid as selective cyclooxygenase-2 inhibitors. Bioorg Med Chem Lett 12:521-4
Weisenseel, Jason P; Reddy, G Ramachandra; Marnett, Lawrence J et al. (2002) Structure of the 1,N(2)-propanodeoxyguanosine adduct in a three-base DNA hairpin loop derived from a palindrome in the Salmonella typhimurium hisD3052 gene. Chem Res Toxicol 15:140-52
Sekhar, Konjeti R; Spitz, Douglas R; Harris, Stephanie et al. (2002) Redox-sensitive interaction between KIAA0132 and Nrf2 mediates indomethacin-induced expression of gamma-glutamylcysteine synthetase. Free Radic Biol Med 32:650-62
Weisenseel, Jason P; Reddy, G Ramachandra; Marnett, Lawrence J et al. (2002) Structure of an oligodeoxynucleotide containing a 1,N(2)-propanodeoxyguanosine adduct positioned in a palindrome derived from the Salmonella typhimurium hisD3052 gene: Hoogsteen pairing at pH 5.2. Chem Res Toxicol 15:127-39
Nemeth, J F; Hochgesang Jr, G P; Marnett, L J et al. (2001) Characterization of the glycosylation sites in cyclooxygenase-2 using mass spectrometry. Biochemistry 40:3109-16
Boutaud, O; Brame, C J; Chaurand, P et al. (2001) Characterization of the lysyl adducts of prostaglandin H-synthases that are derived from oxygenation of arachidonic acid. Biochemistry 40:6948-55
Schnetz-Boutaud, N C; Saleh, S; Marnett, L J et al. (2001) The exocyclic 1,N2-deoxyguanosine pyrimidopurinone M1G is a chemically stable DNA adduct when placed opposite a two-base deletion in the (CpG)3 frameshift hotspot of the Salmonella typhimurium hisD3052 gene. Biochemistry 40:15638-49
Riggins, J N; Marnett, L J (2001) Mutagenicity of the malondialdehyde oligomerization products 2-(3'-oxo-1'-propenyl)-malondialdehyde and 2,4-dihydroxymethylene-3-(2,2-dimethoxyethyl)glutaraldehyde in Salmonella. Mutat Res 497:153-7

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