Prof. Maria Tomasz

Maria Tomasz
Distinguished Professor Emerita

Born: Szeged, Hungary
Address: Dept. of Chemistry, Hunter College, City University of New York, New York, NY 10065
Office: Room 1407A, Hunter North
Laboratory: Room 1410, Hunter North
Telephone:   Office: (212) 772-5387, Chemistry Office: (212) 772-5330
                    FAX Chemistry Office: (212) 772-5332
e-mail:           mtomasz@hunter.cuny.edu
Note: As of October 2007, Prof. Tomasz's research laboratory will be closed. No students will be accommodated for research from that date on.

Educational Record
- Diploma of Chemistry (Highest Honors), Eotvos Lorand University, Budapest, Hungary, 1956.
- M.A. (Chemistry), Columbia University, New York, 1959.
- Ph.D. (Chemistry), Columbia University, New York, 1962. Thesis advisor: Professor Gilbert Stork.
  Thesis title: Stereospecific total synthesis of griseofulvin.
Professional History
- Postdoctoral Fellow, The Rockefeller University, New York, in the laboratory of Dr. S.W. Pelletier, 1961-62.
- Postdoctoral Fellow, New York University Medical School, New York Department of Biochemistry, in the laboratory of Dr. R.W. Chambers, 1962-64.
- Instructor, same department, 1964-1966.
- Visiting Research Associate, The New York Blood Center, 1966.
- Assistant Professor, Hunter College, City University of New York, Department of Chemistry, 1966-1970.
- Associate Professor, same, 1971-78.
- Professor of Chemistry and Biochemistry, Hunter College and The Graduate School, City University of New York, New York, 1979 to date.
- Member, Center for Study of Gene Structure and Function, Hunter College, City University of New York, 1990 to date.
- Member, Center for Applied Biomedicine and Biotechnology, City University of New York, 1993 to date.
- Distinguished Professor, Hunter College, City Unversity of New York, 1996 to 2004.
- Distinguished Professor Emerita, same institution, 2004-
Honors
- Eugene Higgins Graduate Fellow, Columbia University, 1958-59
- NIH Predoctoral Fellowship, 1960-62
- Sigma Xi, 1963
- MERIT Award, National Cancer Institute, 1988
- Presidential Award for Excellence in Scholarship and Creative Activity, Hunter College, 1991
- Japan Society for the Promotion of Science Invitational Fellowship, 1995
- Distinguished Professor, City University of New York, 1996.
- Fellow, American Association for the Advancement of Science, 2002.

RESEARCH INTEREST:

Interaction of Drugs with DNA. Molecular Basis of the Antitumor Action of the Mitomycins

Our main research interest concerns the mode of action of drugs which bind to DNA covalently as their target. Efforts are focused on the clinically 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 the design and synthesis of new drugs.

PUBLICATIONS SINCE 1997:

H. Maruenda and M. Tomasz, "Antisense Sequence-Directed Cross-Linking of RNA Oligonucleotides by Mitomycin", Anti-Cancer Drug Design, 12, 473-479 (1997).
M. Maliepaard, N.J. deMol, M. Tomasz, D. Gargiulo, L.H.M. Janssen, J.P.M. van Duynhoven, E.J.J. van Velzen, W. Verboom and D.N. Reinhoudt, "Mitosene-DNA adducts. Characterization of two major DNA monoadducts formed by 1,10-bisacetoxy-7-methoxymitosene upon reductive activation", Biochemistry, 36, 9211-9220 (1997).
G. Suresh Kumar, R. Lipman, J. Cummings, and M. Tomasz, "Mitomycin C-DNA adducts generated by DT-diaphorase. Revised mechanism of the enzymatic reductive activation of mitomyin C", Biochemistry, 36, 14128-14136 (1997).
M. Tomasz and Y. Palom, "The mitomycin bioreductive antitumor agents: cross-linking and alkylation of DNA as the molecular basis of their activity", Pharmacol. Ther., 76, 73-87 (1997).
L.A. Ramos, R. Lipman, M. Tomasz, and A.K. Basu, "The major mitomycin C monoadduct is cytotoxic but not mutagenic in Escherichia coli", Chem. Res. Toxicol., 11, 64-69 (1998).
Y. Palom, R. Lipman, S.M. Musser, and M. Tomasz, "A mitomycin-N6-deoxyadenosine adduct isolated from DNA", Chem. Res. Toxicol., 11, 203-210 (1998).
J.M. Allan, B.P. Engleward, A.J. Dreslin, M.D. Wyatt, M. Tomasz, and L.D. Samson, "The Mammalian 3-Methyladenine DNA Glycosylase (Aag) Protects Against the Toxicity and Clastogenicity of Certain Chemotherapeutic DNA Cross-linking Agents", Cancer Res., 58, 3965-3973 (1998).
J. Cummings, V.J. Spanswick, M. Tomasz, and J.F. Smyth, "Enzymology of Mitomycin C Metabolic Activation in Tumor Tissue. Implications for Enzyme-Directed Bioreductive Drug Development", Biochem. Pharmacol., 56, 405-414 (1998).
M. Tomasz, A. Das, M.G.J. Ford, A. Minnock, S.M. Musser, K.S. Tang, and M.J. Waring, "The Purine 2-amino Group as the Critical Recognition Element for Sequence-Specific Alkylation and Cross-Linking of DNA by Mitomycin C", J. Am. Chem. Soc., 120, 11581-11593 (1998).
Y. Palom, M.F. Belcourt, G. Suresh Kumar, H. Arai, M. Kasai, A.C. Sartorelli, S. Rockwell, and M. Tomasz, "Formation of a Major DNA Adduct of the Mitomycin Metabolite 2,7-Diaminomitosene in EMT6 Mouse Mammary Tumor Cells Treated with Mitomycin C", Oncology Res., 10, 509-521 (1998).
A. Das, K.S. Tang, S. Gopalakrishnan, M.J. Waring, and M. Tomasz, "Reactivity of guanine at m5CpG steps in DNA: Evidence for electronic effects transmitted through the basepairs", Chemistry & Biology, 6, 461-471 (1999).
M. Paz, A. Das and M. Tomasz, "Mitomycin C linked to DNA minor groove binding agents: Synthesis, reductive activation, DNA binding and cross-linking properties and in vitro antitumor activity", Bioorg. Med. Chem., 1, 2713-2726(1999).
J. J. Dannenberg and M. Tomasz, "Hydrogen Bond Acid/Base Catalysis. A Density Functional Theory Study of Protonated Guanine-(Substituted) Cytosine Base Pairs as models for nucleophilic Attack on Mitomycin in DNA", J. Am. Chem. Soc., 122, 2062-2068 (2000).
Y. Palom, M. F. Belcourt, S. M. Musser, A. C. Sartorelli, S. Rockwell and M. Tomasz, "Structure of Adduct X, the last Unknown of the Six Major DNA Adducts of Mitomycin C formed in EMT6 Mouse Mammary Tumor Cells", Chem. Res. Toxicol. 13, 479-488 (2000).
Y. Palom, M. F. Belcourt, L.-Q. Tang, S. S. Mehta, A. C. Sartorelli, C. A. Pritsos, K. L. Pritsos, S. Rockwell and M. Tomasz, "Bioreductive metabolism of mitomycin C in EMT6 mouse mammary tumor cells: Cytotoxic and non-cytotoxic pathways, leading to different types of DNA adducts. The effect of dicumarol", Biochem. Pharmacol. 61, 1517-1529 (2001).
G. Subramaniam, G. Suresh Kumar, M. M. Paz, A. Das, Y. Palom, C. C. Clement, D. J. Patel and M. Tomasz, "Solution structure of a guanine-N7-linked complex of the mitomycin metabolite 2,7-diaminomitosene and DNA. Basis of sequence selectivity", Biochemistry, 40, 10473-10484 (2001).
M. M. Paz and M. Tomasz, “Reductive activation of mitomycin A by thiols”, Org. Lett., 3, 2789-2842 (2001).
M.M. Paz , A. Das, Y. Palom, Q-Y He and M. Tomasz, "Selective activation of mitomycin A by thiols to form DNA cross-links and mono-adducts: Biochemical basis for the modulation of mitomycin cytotoxicity by the quinone redox potential", J. Med. Chem. 44, 2834-2842 (2001).
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)
K.M. Holtz, S. Rockwell, M. Tomasz, and A. C. Sartorelli, “Nuclear overexpression of NADH: cytochrome b5 reductase activity increases the cytotoxicity of mitomycin C (MC) and the total number of MC-DNA adducts in Chinese Hamster Ovary Cells.” J. Biol. Chem. 278, 5029-5034 (2003).
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
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).
H. A. Seow, M. F. Belcourt, P. G. Penketh, W. F. Hodnick, M. Tomasz, S. Rockwell, and A. C. Sartorelli, “Nuclear Localization of NADPH:Cytochrome c (P450) Reductase Enhances the Cytotoxicity of Mitomycin C to Chinese Hamster Ovary Cells”. Mol. Pharmacol. 67, 417-423 (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).

LIST OF INVITED BOOK CHAPTERS AND REVIEWS, 1987 TO DATE

"The Reaction of Mitomycin C with DNA", K. Nakanishi, G.L. Verdine and M. Tomasz, in "Biologically Active Natural Products", K. Hostettmann and P.J. Lean, eds., Clarendon Press, Oxford (1987).
"Covalent Crosslinks and Monofunctional Adducts of Mitomycin C in the Minor Groove of DNA", A.K. Chawla, R. Lipman and M. Tomasz, in "Structure and Expression. Vol. 2: DNA and Its Drug Complexes", R.H. Sarma and M.H. Sarma, eds., Adenine Press, Guilford, New York (1987).
"Chemistry of the Mitomycin Antibiotics", R.W. Franck and M. Tomasz, in "Chemistry of Anti-Tumor Agents", D.E.V. Wilman, ed., Blackie and Son/Chapman and Hall, New York (1989).
"Course of Recognition and Covalent Reactions Between Mitomycin C and DNA: Sequence Selectivity of a Cross-Linking Drug", M. Tomasz, H. Borowy-Borowsky, and B.F. McGuinness, in "Molecular Basis of Specificity in Nucleic Acid-Drug Interactions", B. Pullman and J. Jortner, eds., Kluwer Academic Publishers, Dordrecht, The Netherlands (1990).
"Mitomycin C: DNA Sequence Specificity of a Natural DNA Cross-Linking Agent", M. Tomasz, in "Advances in DNA Sequence Specific Agents", vol. I, L.H. Hurley, ed., JAI Press, Greenwich, (1992).
"The Mitomycins: Natural Cross-Linkers of DNA", M. Tomasz in "Molecular Aspects of Anticancer Drug-DNA Interactions", M.J. Waring and S. Neidle, eds., Macmillan Press, London (1993).
"DNA Adducts of the Mitomycins", M. Tomasz, in "DNA Adducts: Identification and Biological Significance", IARC Scientific Publications no. 125, K. Hemminki, A. Dipple, D. E. G. Shuker, D. Segerback, F. F. Kadlubar, and H. Bartsch, eds., International Agency for Research on Cancer, Lyon, France (1994).
"Mitomycin C: Small, Fast, and Deadly (but very selective)," M. Tomasz, in Chemistry and Biology2, 575-579 (1995).
"The Mitomycin Bioreductive Antitumor Agents: Cross-linking and Alkylation of DNA as the Molecular Basis of Their Activity," M. Tomasz and Y. Palom, in Pharmacol. Ther.76, 73-87 (1997).
"DNA-Interacting Drugs Used in Lung Cancer Chemotherapy: Molecular Aspects of their Action". Gniazdowski, M. and Tomasz, M. Current Pneumology 3, 1-17 (1999).