This research proposal attempts to elucidate the mechanism of hormone- induced carcinogenesis. The working hypothesis is that reactive metabolites of diethylstilbestrol (DES) covalently bind to nonhistone nuclear proteins, this binding results in an imbalance in chromatin transcription activity, and thus, play a role in DES-induced hamster renal carcinogenesis. Specific experimental goals are to: 1) measure in vitro and in vivo covalent binding of DES reactive metabolites to nuclear proteins of transcriptionally active chromatin., 2) determine changes n the transcription of DNA using DES-modified and unmodified RNA polymerase, 3) determine the chemical nature of covalent linkage between DES metabolite and nonhistone nuclear protein, 4) purify and characterize nonhistone species adducted to DES reactive metabolites, and 5) Using in vivo modulators of thiols, study changes in the level of nonhistone nuclear protein-DES conjugates, transcription activity, DES oxidative metabolite formation, and renal tumor incidence. Modification caused by DES reactive metabolites in the nuclear nonhistone proteins of transcriptionally active chromatin might alter the regulation of transcription or gene expression and thus, play a role in DES-induced renal carcinogenesis. Results of this study will provide new insights in understanding the mechanism of DES- induced carcinogenesis and will allow for the design and development of chemotherapeutic agents to prevent carcinogenesis.
