Mitomycin C is a natural antitumor antibiotic used in clinical cancer chemotherapy. The broad, long-term objective of the present application is to utilize the recently obtained, detailed information on the structural basis of the bioreductive DNA-alkylating activity of mitomycin C for designing new mitomycin analogs with improved antitumor properties. The designs aim at constructing drugs which will retain the basic reductive bifunctional alkylation mechanism of mitomycin C but will be more efficient as cross-linkers. The new mitomycin analogs will be synthesized by relatively simple chemical transformations of mitomycins A or C. They will be tested for reductive alkylation and cross-linking of DNA and for DNA sequence specificity of the modifications. In addition, the structures of the DNA adducts will be investigated. Cytotoxicity of the new agents to a variety of tumor cells will be determined and a correlation will be sought between their DNA cross-linking activity, measured by alkaline elution in EMT mouse mammary tumor cells, and their cytoxicity. Concomitant and interactive with the design efforts, mechanistic investigations of mitomycin C will continue with respect to DNA alkylation in vitro, basis of the CpG specificity of the cross-link and the """"""""self-reducing"""""""" activity of certain mitomycin C analogs, inducible by thiols. An investigation of repair of model oligonucleotide substrates containing mitomycin adducts by a purified mammalian repair enzyme will be initiated.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA040586-13
Application #
2683444
Study Section
Virology Study Section (VR)
Program Officer
Wong, May
Project Start
1985-07-01
Project End
2001-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
13
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Rathi, Abhilasha V; Cantalupo, Paul G; Sarkar, Saumendra N et al. (2010) Induction of interferon-stimulated genes by Simian virus 40 T antigens. Virology 406:202-11
Cantalupo, Paul G; Sáenz-Robles, Maria Teresa; Rathi, Abhilasha V et al. (2009) Cell-type specific regulation of gene expression by simian virus 40 T antigens. Virology 386:183-91
Pipas, James M (2009) SV40: Cell transformation and tumorigenesis. Virology 384:294-303
Ahuja, Deepika; Rathi, Abhilasha V; Greer, Amy E et al. (2009) A structure-guided mutational analysis of simian virus 40 large T antigen: identification of surface residues required for viral replication and transformation. J Virol 83:8781-8
Wright, Christine M; Chovatiya, Raj J; Jameson, Nora E et al. (2008) Pyrimidinone-peptoid hybrid molecules with distinct effects on molecular chaperone function and cell proliferation. Bioorg Med Chem 16:3291-301
Zhao, Xiaorong; Madden-Fuentes, Ramiro J; Lou, Becky X et al. (2008) Ataxia telangiectasia-mutated damage-signaling kinase- and proteasome-dependent destruction of Mre11-Rad50-Nbs1 subunits in Simian virus 40-infected primate cells. J Virol 82:5316-28
Saenz-Robles, M T; Toma, D; Cantalupo, P et al. (2007) Repression of intestinal drug metabolizing enzymes by the SV40 large T antigen. Oncogene 26:5124-31
Ahuja, Deepika; Saenz-Robles, M Teresa; Pipas, James M (2005) SV40 large T antigen targets multiple cellular pathways to elicit cellular transformation. Oncogene 24:7729-45
Cantalupo, Paul; Doering, Adrienne; Sullivan, Christopher S et al. (2005) Complete nucleotide sequence of polyomavirus SA12. J Virol 79:13094-104
Markovics, Jennifer A; Carroll, Patrick A; Robles, M Teresa Saenz et al. (2005) Intestinal dysplasia induced by simian virus 40 T antigen is independent of p53. J Virol 79:7492-502

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