Glutathione Generators in Cancer Chemoprevention

The objective of this research is to design and synthesize certain compounds that will stimulate the biosynthesis of glutathione (GSH). We will also evaluate the potential of the compounds as adjuvant chemopreven- tive agents when used alone and in combination with glutathione S-transferase (GST) inducers. The Phase I specific aims are 1) To synthesize some prototype prodrugs as simulators of GSH biosynthesis, 2) To determine the levels of GSH and the activity of GST in selected tissues of mice after administration of these prodrugs, and 3) To study the GSH levels and GST activities in tissues of mice following the administration of these prodrugs in combination with inhibitors of carcinogenesis that are known to induce GST activity. Inducers of GST, an enzyme that catalyzes the conjugation of GSH with metabolically generated reactive species, have been shown to protect animals against chemically induced tumorigenesis. Thus, elevations of GST activity concomitant with an increase in cellular GSH level constitute a powerful detoxifying response against xenobiotics. This research project is designed to test the concept that the combination of GST inducers and GSH generators constitute a viable new chemopreventive approach to combat cancer.