Research Summary - Our main research interest concerns the mode of action of drugs which bind to DNA covalently as their target. Efforts are focused on the clinicallly important anticancer agents, the mitomycins. These drugs attach themselves covalently to guanine in DNA. A unique feature is their ability to cross-link DNA between the complementary strands. DNA cross-links represent one of the most lethal types of DNA damage. One of our main goals is to elucidate the covalent chemistry of drug-DNA interactions, to detect specific DNA sequences targeted by the drugs and characterize the consequent three-dimensional alterations of DNA structure. This information is used to elucidate the molecular basis of the observed biological effects of the mitomycins, e.g. DNA repair, inhibition of DNA replication and selective cytotoxicity to tumor cells. Another related area of our investigation is the bioactivation of mitomycins by flavoreductase enzymes. Such processes are fundamentally related to the action of numerous important antitumor drugs. Our analysis of the mode of action of known anticancer drugs leads to rational, mechanism-based design and synthesis of new drugs.

Selected publications

T. Abbas, M. Olivier, J. Lopez, S. Houser, G. Xiao, G. Suresh Kumar, M.Tomasz, J.Bargonetti, “Differential activation of p53 by the various adducts of mitomycin C” J. Biol. Chem. 277, 40513-9 (2002).

Y . Palom, G. Suresh Kumar, L.Q. Tang, M.M. Paz, S. M. Musser, S. Rockw ell and M. Tomasz, “Relative toxicities of DNA cross-links and monoadducts: New insights from studies of decarbamoyl mitomycin C and mitomycin C.” Chem. Res. Toxicol. 15, 1398-1406 (2002).

M. M. Paz, G. Suresh Kumar, M. Glover, M. J. Waring, and M. Tomasz, “Mitomycin dimers: Polyfunctional cross-linkers of DNA”. J. Med. Chem. 47, 3308-3319 (2004).

H. A. Seow, P. L Penketh, M. F. Belcourt, M. Tomasz, S. Rockwell, and A.C. Sartorelli, “Nuclear Overexpression of NAD(P)H:Quinone Oxidoreductase 1 in Chinese Hamster Ovary Cells Increases the Cytotoxicity of Mitomycin C Under Aerobic and Hypoxic Conditions”J. Biol. Chem. 279, 31606-31612 (2004).

C. D. Utzat, C. C. Clement, L. A. Ramos, A. Das, M. Tomasz, and A. K. Basu “The DNA adduct of the Mitomycin C Metabolite 2,7-Diaminomitosene is a Non-Toxic and Non-Mutagenic DNA Lesion in Vitro and in Vivo”. Chem. Res. Toxicol. 18, 213-223 (2005).

E. K. Boamah, D. E. White, K. E. Talbott. N. C. Arva. D. Berman, M. Tomasz, and J. Bargonetti, “Mitomycin-DNA Adducts Induce p53-Dependent and p53-Independent Cell Death Pathways”, ACS Chemical Biology 2, 399-407 (2007).