Selective inhibition of MCF-7(piGST) breast tumors using glutathione transferase-derived 2-methylene-cycloalkenones.
Human glutathione (GSH) transferase (hGSTP1-1) catalyzes the conversion of antitumor 2-crotonyloxymethyl-2-cycloalkenones (COMCs) to highly reactive exocyclic enone alkylating agents. In vitro efficacy studies show that the cytotoxicities of the COMCs directly correlate with the level of expression of GSTP1-1 in MCF-7(piGST) versus MCF-7wt breast tumors, indicating that the exocyclic enones are the actual cytotoxic species. The COMCs are a potentially important new class of prodrugs, which can specifically target multi-drug-resistant tumors overexpressing hGSTP1-1.
Joseph
Erin
E
Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, MD 21250, USA.
Ganem
Bruce
B
Eiseman
Julie L
JL
Creighton
Donald J
DJ
D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D003512:Cyclohexanones / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D051549:Glutathione S-Transferase pi / Q000096:biosynthesis*; D006801:Humans; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D018906:Antineoplastic Agents, Alkylating; D003512:Cyclohexanones; D011355:Prodrugs; C073431:2-crotonyloxymethyl-2-cyclohexenone; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi