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 #
1R35CA047479-01
Application #
3479680
Study Section
(SRC)
Project Start
1988-05-01
Project End
1989-04-30
Budget Start
1988-05-01
Budget End
1989-04-30
Support Year
1
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

Name
Wayne State University
Department
Type
Schools of Arts and Sciences
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202

  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
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
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
Boutaud, O; Li, J; Chaurand, P et al. (2001) Oxygenation of arachidonic acid by cyclooxygenases generates reactive intermediates that form adducts with proteins. Adv Exp Med Biol 500:133-7
Fink, S P; Marnett, L J (2001) The relative contribution of adduct blockage and DNA repair on template utilization during replication of 1,N2-propanodeoxyguanosine and pyrimido. Mutat Res 485:209-18
Ji, C; Amarnath, V; Pietenpol, J A et al. (2001) 4-hydroxynonenal induces apoptosis via caspase-3 activation and cytochrome c release. Chem Res Toxicol 14:1090-6
Ji, C; Kozak, K R; Marnett, L J (2001) IkappaB kinase, a molecular target for inhibition by 4-hydroxy-2-nonenal. J Biol Chem 276:18223-8

Showing the most recent 10 out of 126 publications