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Inhibition of Estrogen-induced Renal Carcinogenesis in Male Syrian Hamsters by Tamoxifen without Decrease in DNA Adduct Levels¹

Departments of Pharmacology and Toxicology [J. G. L.] and Pathology [E. J.], University of Texas Medical Branch, Galveston, Texas 77550; Department of Biochemistry and Molecular Biology, University of Texas Medical School, Houston, Texas 77225 [D. A. S.]; and Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030 [E. R., K. R.]

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, 17ß-estradiol and the antihormone tamoxifen were concomitantly administered as S.C. implants to male Syrian hamsters. 17ß-Estradiol-treated and tamoxifen-treated animals served as positive and negative controls, respectively. The tumor incidence decreased from 100% in 17ß-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 17ß-estradiol and 17ß-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 17ß-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.

¹ This work was supported in part by grants from the National Cancer Institute, NIH [CA 43232, CA 43233, CA 44069, CA 32157, CA 10893 (P6), CA 26617, CA 38024], and from the American Cancer Society [BC-255].

² To whom requests for reprints should be addressed.

Received 3/24/87. Revised 10/21/87. Accepted 11/13/87.

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