Inhibition of Tumor Cells that Over-Express nGST
Abstract
In the second year of this three year project, we have discovered an additional class of molecules that will serve as substrates for human glutathione transferase, producing as products cytotoxic alkylating agents of nucleic acids and/or proteins critical to cell function. This provides additional evidence that it is possible to make antitumor prodrugs that will selectively kill multidrug resistant breast cancer cells by using glutathione transferase as a drug factory inside tumor cells. Specifically we have demonstrated that (a) the glutathione conjugate of 2-crotonyloxymethyl-2-cyclohexenone (COMC) is unlikely to fully account for in vitro antitumor activity of COMC, (b) that COMC, in the presence of glutathione, undergoes glutathione transferase (GSTP 1 1)-catalyzed conversion to a reactive exocyclic enone species, and (c) this species covalently modifies model nucleic acids, which is the likely basis for the tumor toxicity of COMC. We are now in the process of testing the in vitro tumoricidal activities of COMC and related compounds, in collaboration with Dr. Julie Eiseman, University of Pittsburgh Cancer Center.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2001
- Accession Number
- ADA396686
Entities
People
- Donald J. Creighton
Organizations
- University of Maryland, Baltimore