Mammary gland (MG) carcinogenesis in the rat, chemically induced, has many similarities to human breast cancer. N- Arylhydroxamic acids induced MG tumors (epithelial and stromal) in female rats after systemic or direct application and sarcomas at injection sites. These carcinogens require activation to form covalent DNA adducts considered critical for initiation. One possible route to activation may be via peroxidases, intracellular and leukocytic. These peroxidases catalyze le-oxidation and/or halide-dependent oxidative cleavage or N-hydroxy-N-2- fluorenylacetamide (N-OH-2-FAA) to yield N-acetoxy-2-FAA and/or 2-nitrosofluorene (2-NOF), both of which are carcinogenic. 2-NOF is also an extremely potent direct mutagen. Both products, N-AcO-2-FAA directly and 2-NOF indirectly, react covalently with DNA. We propose to continue our investigation of peroxidative activation of N-fluorenyl-hydroxamic acids under the following specific aims: 1) To further characterize haloperoxidase-mediated oxidations of N-OH-2-FAA, and related carcinogens N-OH-3-FAA and N-hydroxy-N-2-fluorenylbenzamide (N-OH-2-FBA) using myeloperoxidase to investigate Br- vs Cl- specificity and lactoperoxidase to investigate I--dependent oxidations vs ring iodinations; 2) To further investigate the oxidation of N-OH-2-FAA by ubiquitous prostaglandin hydroperoxide synthase; 3) To increase peroxidative activity in the rat MG to facilitate metabolic studies; 4) To concurrently determine N,O-acyl-transferase activity in the rat MG since it may contribute to activation of N-OH-2-FAA; 5) To further increase the specific activity of MG peroxidase via chromatographic purification; 6) To characterize the partially purified MG peroxidase with respect to substrate, inhibitor and halide specificities, and by comparison to uterine and eosinophil peroxidase; 7) To determine if nucleic acid adducts are formed from N-fluorenylhydroxamic acids peroxidative conditions of le- oxidation and halide-dependent oxidative cleavage at the intermediate or product stage; 8) To determine the peroxidative activities in the rat peritoneal fluid and serosa; and to determine in vivo metabolites of the carcinogens N-OH-2-FAA and N-OH-2- FBA in peritoneal fluid. The chief methodologies to be used in the proposed studies ar HPLC, FPLC, UV spectrometry, affinity chromatography, and gel electrophoresis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA028000-11
Application #
3482103
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1980-04-01
Project End
1993-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
11
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Malejka-Giganti, Danuta; Bennett, Kristen K; Culp, Sandra J et al. (2005) Suppression of 7,12-dimethylbenz[a]anthracene-induced mammary carcinogenesis by pre-initiation treatment of rats with beta-naphthoflavone coincides with decreased levels of the carcinogen-derived DNA adducts in the mammary gland. Cancer Detect Prev 29:338-47
Ritter, Clare L; Culp, Sandra J; Freeman, James P et al. (2002) DNA adducts from nitroreduction of 2,7-dinitrofluorene, a mammary gland carcinogen, catalyzed by rat liver or mammary gland cytosol. Chem Res Toxicol 15:536-44
Horn, Thomas L; Reichert, Mark A; Bliss, Robin L et al. (2002) Modulations of P450 mRNA in liver and mammary gland and P450 activities and metabolism of estrogen in liver by treatment of rats with indole-3-carbinol. Biochem Pharmacol 64:393-404
Ritter, C L; Prigge, W F; Reichert, M A et al. (2001) Oxidations of 17beta-estradiol and estrone and their interconversions catalyzed by liver, mammary gland and mammary tumor after acute and chronic treatment of rats with indole-3-carbinol or beta-naphthoflavone. Can J Physiol Pharmacol 79:519-32
Ritter, C L; Decker, R W; Malejka-Giganti, D (2000) Reductions of nitro and 9-Oxo groups of environmental nitrofluorenes by the rat mammary gland in vitro. Chem Res Toxicol 13:793-800
Malejka-Giganti, D; Niehans, G A; Reichert, M A et al. (2000) Post-initiation treatment of rats with indole-3-carbinol or beta-naphthoflavone does not suppress 7, 12-dimethylbenz[a]anthracene-induced mammary gland carcinogenesis. Cancer Lett 160:209-18
Brauze, D; Malejka-Giganti, D (2000) A novel 4 S [3H]beta-naphthoflavone-binding protein in liver cytosol of female Sprague-Dawley rats treated with aryl hydrocarbon receptor agonists. Biochem J 347 Pt 3:787-95
Malejka-Giganti, D; Niehans, G A; Reichert, M A et al. (1999) Potent carcinogenicity of 2,7-dinitrofluorene, an environmental pollutant, for the mammary gland of female Sprague-Dawley rats. Carcinogenesis 20:2017-23
Ritter, C L; Malejka-Giganti, D (1998) Nitroreduction of nitrated and C-9 oxidized fluorenes in vitro. Chem Res Toxicol 11:1361-7
Brauze, D; Crow, J S; Malejka-Giganti, D (1997) Modulation by beta-naphthoflavone of ovarian hormone dependent responses in rat uterus and liver in vivo. Can J Physiol Pharmacol 75:1022-9

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