The elucidation of the mechanism of induction of renal clear-cell carcinoma in male Syrian hamsters by diethylstilbestrol (DES) is attempted. Since estrogen alone induced kidney tumors in these animals, it is suspected that DES both initiates and promotes carcinogenesis. The following phases of tumor initiation and/or tumor promotion by estrogen will be investigated: 1. Identification of the enzyme system responsible for oxidation of DES to DES quinone in hamster kidney. DES quinone is a reactive intermediate suspected to be the ultimate carcinogen. 2. Investigation of possible intercalation by DES quinone. 3. Isolation and identification of DES quinone-DNA adducts and comparison with microsome-mediated DES-DNA adducts formed in vitro. 4. Determination of time periods of tumor initiation and of tumor promotion by pelleting male hamsters in vivo initially with DES and then, after removal of DES, with 2-fluoroestradiol. 2-Fluorestradiol does not induce tumors, but due to its high estrogenic activity it is suspected to act as a tumor promoter. 5. Measurements of induction of ornithine decarboxylase and polyamine synthesis by DES and 2-fluorestradiol in vivo. 6. Establishment of a primary cell culture derived from Syrian hamster kidney. 7. Investigation of binding of DES and DES quinone to DNA in kidney cell culture. 8. Investigation of DNA repair activity in primary kidney cell culture. 9. Induction of ornithine decarboxylase in cell culture by 2-fluoroestradiol and/or estrogen-induced pituitary growth factors from pituitary extracts. 10. Attempted induction of growth of cultured kidney cells after exposure to DES or DES quinone. Growth factors for these cells are expected to be present in pituitary extracts from estrogen-treated hamsters.
