Inhibition of Tumor cells that Over-Express nGST

摘要

In the third and final year of this three year project, we have characterized 2crotonyl-oxymethyl-2- cyclohexenone (COMC-6) and its derivatives as substrates for human glutathione transferase (hGST), producing as products cytotoxic alkylating agents of nucleic acids and/or proteins critical to cell function. Compounds of this type should be potent antitumor agents against breast cancer cells over expressing GST as part of the multidrug resistance phenotype. Specifically, we have (a) discovered that hGSTP1-1 efficiently catalyzes the conversion of COMC-6 to a reactive exocyclic enone of COMC-6, (b) shown that the exocyclic enone can alkylate oligonucleotides in vitro--the probable basis of antitumor activity (c) synthesized and characterized the 5- and 7-membered ring homologues of COMC-6 (COMC-5, COMC-7) and demonstrated that COMC-6 is more potent to B16 tumor cells than COMC-6 in vitro, and (d) demonstrated that COMC-6 displays similar toxicities to human colon HT29 versus HT29 over-expressing the phosphoglycoprotein responsible for some type of multidrug resistance. We are now in the process of testing the in vitro tumoricidal activities of COMC-6 and its homologes to MCF-7 breast tumor cells versus MCF-7 over-expressing hGSTP1-1.