Recently we have established that high-energy tandem mass spectrometry is sufficiently specific for determining structure of DNA adducts. When coupled with fast atom bombardment mass spectrometry, however, the detection limits and sensitivity are not adequate to support investigations of adducts in the femtomole range. To overcome this limitation, we propose to develop and compare three mass spectrometric approaches for high- sensitivity detection and structure determination of DNA adducts. Tandem foursector mass spectrometry with extended array detection has recently been coupled with electrospray ionization in our laboratory. Continued development is the highest priority because the product-ion spectra have sufficient specificity to distinguish isomeric adducts. Efforts will be extended to understand the basic ions chemistry that underpins these collisionally activated dissociation spectra. In parallel, we will use routine triple quadrupole mass spectrometry coupled via electrospray ionization with HLPLC. The low-energy collisionally induced fragmentations that are endemic to the triple quadrupole will be evaluated and compared with those occurring under the high-energy conditions of the four-sector instrument. The third approach is matrix-assisted laser desorption ionization (MALDI), which will be developed as a screening approach and as a structure-verification method by means of both molecular-ion and post- source=decomposition monitoring. In addition. MALDI capabilities will be extended to studies in which sites of modification and depurination in oligonucleotides must be located. The overall goal is to establish the merits of various mass spectrometric approaches to structure determination of DNA adducts, to understand the underlying ion chemistry, and to apply appropriately the methods to samples isolated from in vitro and in vivo studies.
| 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 |
| 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 |
| 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 |
| 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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