Inhibition of estrogen-induced renal carcinogenesis in male Syrian hamsters by tamoxifen without decrease in DNA adduct levels.
Estrogens have previously been shown to induce covalent DNA modifications specifically in the hamster kidney, the target organ of estrogen-inducible and -dependent renal carcinoma. The DNA adducts, formed by yet unknown mechanisms, have been postulated to mediate hormonal carcinogenesis in this animal model. In an attempt to study a possible involvement of estrogen receptor mechanisms in the formation of DNA adducts, 17 beta-estradiol and the antihormone tamoxifen were concomitantly administered as s.c. implants to male Syrian hamsters. 17 beta-Estradiol-treated and tamoxifen-treated animals served as positive and negative controls, respectively. The tumor incidence decreased from 100% in 17 beta-estradiol-treated controls to 25% in the group receiving tamoxifen in addition to hormone. Tamoxifen-treated animals did not develop kidney tumors and did not show any detectable DNA damage. DNA adduct levels were comparable in hamsters treated with 17 beta-estradiol and 17 beta-estradiol plus tamoxifen for 5 or 7 months. In hamsters inoculated with H-301 cells, which are derived from the estrogen-induced hamster renal carcinoma and are estrogen dependent for growth, tamoxifen decreased estrogen-dependent H-301 tumor growth. However, in cell culture, neither 17 beta-estradiol nor tamoxifen influenced H-301 cell division. It was concluded that tamoxifen inhibited the growth of estrogen-induced renal carcinoma but did not interfere with tumor initiation since it did not inhibit the formation of DNA adducts. Moreover, receptor mechanisms were most probably not involved in the induction of DNA modifications by estrogens.
Liehr
J G
JG
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77550.
Sirbasku
D A
DA
Jurka
E
E
Randerath
K
K
Randerath
E
E
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D004247:DNA / Q000378:metabolism*; D004958:Estradiol; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D007700:Kinetics; D008297:Male; D008647:Mesocricetus; D013629:Tamoxifen / Q000627:therapeutic use*
D013629:Tamoxifen; D004958:Estradiol; D004247:DNA