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.
| 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; Saeed, Muhammad; Lu, Fang et al. (2007) Inhibition of catechol-O-methyltransferase increases estrogen-DNA adduct formation. Free Radic Biol Med 43:1534-40 |
| Gaikwad, Nilesh W; Rogan, Eleanor G; Cavalieri, Ercole L (2007) Evidence from ESI-MS for NQO1-catalyzed reduction of estrogen ortho-quinones. Free Radic Biol Med 43:1289-98 |
| 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 |
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