Abstract

Our first aim is to determine the structure of several covalent adducts of mitomycin C (MC), a clinically used antitumor agent, formed with deoxyguanosine. We isolated such adducts recently from model reactions and from reactions of activated MC with DNA. Structural investigations of recently obtained putative """"""""crosslink"""""""" type adducts are also planned. Another aim is development of a consolidated scheme of degradation of MC-modified DNA, followed by HPLC analysis, which can be used as a sensitive mapping assay of adducts from various DNAs. A further aim is application of this assay to DNA modified by MC in vivo or in tissue cultures. These studies are expected to provide information about the mode of cytotoxicity and antitumor selectivity of MC. In the long range, the assay offers a method to attack problems in general in the area of MC repair, cytotoxicity, mutagenicity, chromosomal alterations, etc., leading to understanding of these biological effects of MC in molecular terms.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA028681-07
Application #
3168258
Study Section
Biochemistry Study Section (BIO)
Project Start
1980-07-01
Project End
1988-06-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
7
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

Name
Hunter College
Department
Type
Schools of Arts and Sciences
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10065

  Publications

Paz, Manuel M; Ladwa, Sweta; Champeil, Elise et al. (2008) Mapping DNA adducts of mitomycin C and decarbamoyl mitomycin C in cell lines using liquid chromatography/ electrospray tandem mass spectrometry. Chem Res Toxicol 21:2370-8
Champeil, Elise; Paz, Manuel M; Ladwa, Sweta et al. (2008) Synthesis of an oligodeoxyribonucleotide adduct of mitomycin C by the postoligomerization method via a triamino mitosene. J Am Chem Soc 130:9556-65
Boamah, Ernest K; White, David E; Talbott, Kathryn E et al. (2007) Mitomycin-DNA adducts induce p53-dependent and p53-independent cell death pathways. ACS Chem Biol 2:399-407
Paz, Manuel M; Kumar, Gopinatha Suresh; Glover, Mark et al. (2004) Mitomycin dimers: polyfunctional cross-linkers of DNA. J Med Chem 47:3308-19
Abbas, Tarek; Olivier, Magali; Lopez, Jaqueline et al. (2002) Differential activation of p53 by the various adducts of mitomycin C. J Biol Chem 277:40513-9
Palom, Yolanda; Suresh Kumar, Gopinatha; Tang, Li-Qian et al. (2002) Relative toxicities of DNA cross-links and monoadducts: new insights from studies of decarbamoyl mitomycin C and mitomycin C. Chem Res Toxicol 15:1398-406
Paz, M M; Das, A; Palom, Y et al. (2001) Selective activation of mitomycin A by thiols to form DNA cross-links and monoadducts: biochemical basis for the modulation of mitomycin cytotoxicity by the quinone redox potential. J Med Chem 44:2834-42
Paz, M M; Tomasz, M (2001) Reductive activation of mitomycin A by thiols. Org Lett 3:2789-92
Subramaniam, G; Paz, M M; Suresh Kumar, G et al. (2001) Solution structure of a guanine-N7-linked complex of the mitomycin C metabolite 2,7-diaminomitosene and DNA. Basis of sequence selectivity. Biochemistry 40:10473-84
Paz, M M; Das, T A; Tomasz, M (1999) 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 7:2713-26

Showing the most recent 10 out of 45 publications