The objective of this competing continuation application is to delineate the structure activity relationships and mechanisms of activation leading to tumorigenesis by nitrofluorenes and nitro-9-fluorenones. These environmental pollutants cause mammary tumors in rats. The hypothesis to be tested is that tumorigenic potency depends on metabolic activation, which is in turn determined by the position of nitro groups and oxidation status of C9 of the fluorene. Activation is proposed to occur by a combination of nitro reduction and hydroxylamine activation, free radicals from redox cycling of nitroso and nitrofluorenes, and sulfation of C9-hydroxyl groups.
The specific aims are: 1) To evaluate the relative potencies of nitrofluorenes and their 9-hydroxy and 9-oxo derivatives following intramammary administration to rats in vivo. 2) To evaluate the capacity of rat mammary adipocyte and epithelial/stromal tissues to activate nitrofluorenes by one or two electron reductions in vitro. Reactivity of putative intermediates with deoxynucleosides in solution will be characterized, as will the capacity of redox intermediates to generate oxygen free radicals and initiate lipid peroxidation. 3) To determine the capacity of rat mammary microsomes to bioactivate fluorenes by C-9 hydroxylation, to determine the mutagenicity of C9-oxidized fluorenes in Salmonella typhimurium and to investigate the bioactivation of C9-oxidized fluorenes by rat liver sulfotransferases. 4) To identify DNA adducts formed in vivo from the bioactivation of nitrofluorenes, C9-oxidized fluorenes, and lipid peroxidation-derived malondialdehyde following intramammary instillation of the test compounds.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA028000-18
Application #
2633724
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Liu, Yung-Pin
Project Start
1980-04-01
Project End
2000-12-31
Budget Start
1998-01-01
Budget End
1998-12-31
Support Year
18
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pathology
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
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, 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
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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