The major goal of this proposal is to increase our understanding of the underlying mechanism(s) involved in estrogen carcinogenesis. The production of free radical species has been postulated to be associated with several human pathological conditions, including hormonal carcinogenesis and neuronal degradation, and is also the consequence of metabolism of several xenobiotics and antineoplastic agents. The experimental approach to attain this goal is made possible by the recent successes in our laboratories in the isolation and stabilization of estrone-3, 4-quinone (3,4-EQ) and other ortho-quinones, as well as the observation that 3,4-EQ induces single strand- but not double-strand DNA breaks. Collectively, these findings present a unique opportunity to integrate the expertise of the key scientific personnel involved in these diverse areas in an effort to achieve the following specific objectives: 1. Synthesize and secure estrogen o-quinones and other important compounds having the catechol/o-quinone group in their structure. 2. Characterize the type, specificity and repair of DNA damage induced in human cells treated with o-quinones. 3. Elucidate cellular biochemical determinants mediating the metabolism of o-quinones to DNA damaging species. 4. Identify o-semiquinones and oxyradicals eliciting DNA damage in o- quinone-treated human cells using electron spin resonance spectroscopy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA057615-01
Application #
3201964
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1992-08-01
Project End
1996-07-31
Budget Start
1992-08-01
Budget End
1993-07-31
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
Schools of Pharmacy
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Akanni, A; Abul-Hajj, Y J (1997) Estrogen-nucleic acid adducts: reaction of 3,4-estrone-o-quinone radical anion with deoxyribonucleosides. Chem Res Toxicol 10:760-6
Roy, D; Abul-Hajj, Y J (1997) Estrogen-nucleic acid adducts: guanine is major site for interaction between 3,4-estrone quinone and COIII gene. Carcinogenesis 18:1247-9
Akanni, A; Tabakovic, K; Abul-Hajj, Y J (1997) Estrogen-nucleic acid adducts: reaction of 3,4-estrone o-quinone with nucleic acid bases. Chem Res Toxicol 10:477-81
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Akkani, A; Paterlini, G; Gleason, W B et al. (1997) 6 beta-Propynyl-substituted steroids: mechanism-based enzyme-activated irreversible inhibitors of aromatase. J Med Chem 40:3263-70
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Abul-Hajj, Y J; Tabakovic, K; Gleason, W B et al. (1996) Reactions of 3,4-estrone quinone with mimics of amino acid side chains. Chem Res Toxicol 9:434-8
Nutter, L M; Wu, Y Y; Ngo, E O et al. (1994) An o-quinone form of estrogen produces free radicals in human breast cancer cells: correlation with DNA damage. Chem Res Toxicol 7:23-8
Khasnis, D; Abul-Hajj, Y J (1994) Estrogen quinones: reaction with propylamine. Chem Res Toxicol 7:68-72
Nutter, L M; Zhou, B; Sierra, E E et al. (1994) Cellular biochemical determinants modulating the metabolism of estrone 3,4-quinone. Chem Res Toxicol 7:609-13

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