The major achievement during the current grant period has been the discovery of a relationship between depurinating DNA adducts, which generate apurinic sites, an the Harvey (H)-ras mutations in mouse skin papillomas induced by benzo[a]pyrene (BP), dibenzo[DB[alpha, l]P) and 7,12- dimethyl-benz[alpha]anthracene. The first goal during the continuation period is to extend the correlation between depurinating adducts and oncogenic mutations by determining the profiles of stable and depurinating adducts of selected PAH and comparing them with mutations in the H-ras gene. We also propose that estrogen metabolites, catechol estrogen quinones (CE-3,4-Q), are endogenous tumor initiators by forming depurinating N7Gua adducts. The second goal is to determine the role of depurinating CE-DNA adducts by analyzing DNA adducts in male hamsters (susceptible to estrogen-induced renal tumor) treated with estrogens or their metabolites. The third goal is to identify the sites of stable adducts and apurinic sites in specific DNA sequences treated with activated PAH or CE and to relate the lesions to mutations. Fourth, we will develop monoclonal antibodies to depurinating adducts of BP, DB[alpha,l]P and CE- 3,4-Q, validate immunochemical assays and conduct transitional epidemiological studies by using the antibodies as molecular dosimeters. Fifth, we will use fluorescence line narrowing spectroscopy for (a) identifying PAH-DNA adducts, (b) determining adduct conformations and assessing adduct repair rates as a function of conformation, and (c) monitoring formation and repair of apurinic sites by means of specific fluorescent tags. The final goal is to use our recently improved mass spectrometry (MS) techniques to understand the ion chemistry of DNA adducts and to develop electrospray/tandem MS to analyze DNA adducts and MALDI MS to analyze DNA adducts and modified oligonucleotides. In all these studies we will develop and apply frontline technology to test whether (1) depurinating DNA adducts lead to tumor initiation by generating oncogenic mutations and (2) CE-3,4-Q are endogenous tumor initiators that could be at the origin of a variety of human cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA049210-11
Application #
2894791
Study Section
Cancer Centers and Research Programs Review Committee (CCRP)
Program Officer
Liu, Yung-Pin
Project Start
1988-12-01
Project End
2001-04-30
Budget Start
1999-05-01
Budget End
2001-04-30
Support Year
11
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
Cavalieri, Ercole; Saeed, Muhammad; Zahid, Muhammad et al. (2012) Mechanism of DNA depurination by carcinogens in relation to cancer initiation. IUBMB Life 64:169-79
Zahid, Muhammad; Saeed, Muhammad; Rogan, Eleanor G et al. (2010) Benzene and dopamine catechol quinones could initiate cancer or neurogenic disease. Free Radic Biol Med 48:318-24
Saeed, Muhammad; Rogan, Eleanor; Cavalieri, Ercole (2009) Mechanism of metabolic activation and DNA adduct formation by the human carcinogen diethylstilbestrol: the defining link to natural estrogens. Int J Cancer 124:1276-84
Saeed, Muhammad; Higginbotham, Sheila; Gaikwad, Nilesh et al. (2009) Depurinating naphthalene-DNA adducts in mouse skin related to cancer initiation. Free Radic Biol Med 47:1075-81
Lu, Fang; Zahid, Muhammad; Wang, Cheng et al. (2008) Resveratrol prevents estrogen-DNA adduct formation and neoplastic transformation in MCF-10F cells. Cancer Prev Res (Phila Pa) 1:135-45
Gaikwad, Nilesh W; Yang, Li; Muti, Paola et al. (2008) The molecular etiology of breast cancer: evidence from biomarkers of risk. Int J Cancer 122:1949-57
Chakravarti, Dhrubajyoti; Venugopal, Divya; Mailander, Paula C et al. (2008) The role of polycyclic aromatic hydrocarbon-DNA adducts in inducing mutations in mouse skin. Mutat Res 649:161-78
Zahid, Muhammad; Gaikwad, Nilesh W; Rogan, Eleanor G et al. (2007) Inhibition of depurinating estrogen-DNA adduct formation by natural compounds. Chem Res Toxicol 20:1947-53
Montano, M M; Chaplin, L J; Deng, H et al. (2007) Protective roles of quinone reductase and tamoxifen against estrogen-induced mammary tumorigenesis. Oncogene 26:3587-90
Zhang, Yan; Gaikwad, Nilesh W; Olson, Kevin et al. (2007) Cytochrome P450 isoforms catalyze formation of catechol estrogen quinones that react with DNA. Metabolism 56:887-94

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