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Relation to Hormonal Activity and Cell Proliferation1 [CANCER RESEARCH 55, 4347-4351, October 1, 1995] Carcinogenic Activities of Various Steroidal and Nonsteroidal Estrogens in the Hamster Kidney: Relation to Hormonal Activity and Cell Proliferation1 Jonathan J. Li,2 Sara Antonia Li, Terry D. Oberley, and Jonathan A. Parsons Hormonal Carcinogenesis Laboratory, Division of Etiology and Prevention of Hormonal Cancers, University of Kansas Cancer Center, and Department of Pharmacology, Toxicology, and Therapeutics [J. J. L, S. A. L} and Preventive Medicine [J. J. L], University of Kansas Medical Center, Kansas City, Kansas 66160-7312; Pathology Service, William S. Middleton Memorial Veterans Administration Hospital, and Department of Pathology, University of Wisconsin Medical School. Madison, Wisconsin 53706 IT. D. O.J; and Department of Anatomy, University of Minnesota Medical School, Minneapolis, Minnesota 55417 ¡J.A. P.} ABSTRACT INTRODUCTION The therapeutic use of estrogens has been associated with an increased Numerous epidemiological studies have established causal relation risk of some of the most predominant, as well as less prevalent, cancers in ships between estrogen use and increased risk for some of the pre women. The estrogen-induced renal tumor is one of the primary animal dominant cancers in women, namely, breast and endometrium (1-3). models to evaluate the carcinogenic properties of estrogens. Correlations Ingestion of estrogens has also been associated with some less prev were made with various estrogens by using parameters of estrogenicity alent cancers at hepatic, cervico-vaginal, and ovarian sites (4-6). It is end points such as competitive binding, progesterone receptor induction, estimated that at least 20 million women in the United States take and alterations in prolactin levels; in vitro renal proximal cell prolifera estrogenic hormones, largely but not solely for contraception, for the tion; and in vivo estrogen-induced carcinogenicity. The most potent estro relief of menopausa! symptoms, and to reduce the risk of osteoporosis gens were Moxestrol (MOX), diethylstilbestrol (DES), and 17ß-estradiol, and cardiovascular disease that afflicts aging women. On a worldwide followed by indenestrol B, 16a-hydroxyestrone, and llß-methoxyestra- basis, this number is most certainly multiplied many times. Menopau- diol with moderate estrogenic activities, whereas llß-methylestradiol, sal estrogens have become one of the most widely prescribed drugs, 17a-estradiol, indanestrol, and deoxoestrone were all relatively weaker. with a current usage rate of over 32% among women ages 50-70 As expected, hydrolyzed Premarin (unconjugated estrogens) was strongly years (7). Despite increasing study, there is still little understanding of estrogenic. Of the estrogens tested, MOX was the most potent carcino the cellular and molecular mechanisms(s) whereby these estrogen- genic estrogen in the hamster kidney. Both 16a-hydroxyestrone and llß- methoxyestradiol induced intermediate tumor incidences with distinctly related neoplastic events occur. The estrogen-induced renal tumor has emerged as one of the lower frequencies of renal tumor foci compared to the most potent car cinogenic estrogens. However, hamsters treated for 9.0 months with llß- primary experimental models to evaluate the carcinogenic properties methylestradiol, 17a-estradiol, deoxoestrone, and indanestrol exhibited of estrogens, whether they possess steroidal or nonsteroidal structures no tumors. In contrast, treatment with estrone, equilin plus d-equilenin, (8-10). Recent advances in estrogen carcinogenesis indicate that cell and hydrolyzed Premarin for the same time period resulted in 100% renal proliferation may play a critical early role in estrogen-induced tumor- tumor incidences and numerous tumor foci. Cell proliferation studies of igenic processes (11, 12). Interestingly, this concept has received cultured hamster kidney proximal tubule cells were carried out at varying considerable support from earlier studies using numerous experimen estrogen concentrations (0.01-100 nivi). Exposure to MOX resulted in tal models in hormonal carcinogenesis employing estrogens as well as consistently high renal cell proliferative response over a concentration other sex steroids (13-17). range of 0.1-10 n\i. Strongly carcinogenic estrogens such as estrone had a The current report presents data correlating in vivo carcinogenicity maximal renal cell proliferation response (2.4-fold above untreated con data of estrogens and in vitro cell proliferation of primary renal trol levels) between 0.1 and 10 »\i,DES and 17ß-estradiol responded at epithelial hamster cells in culture, grown in serum-free chemically 1.0 UM,and 4-hydroxyestradiol responded at 10 n\i. Interestingly, expo defined conditions, as well as other parameters of estrogenicity. sure to ethinylestradiol, a potent estrogen, at similar or higher doses as those used for DES and 17ß-estradiol, yielded only a 10% renal tumor incidence and induced only a 1.7-fold increase in proximal tubule cell MATERIALS AND METHODS proliferation. In contrast, 17<*-estradiol, deoxoestrone, indanestrol, and llß-methylestradiol, all weakly estrogenic and noncarcinogenic agents, Chemicals and Reagents. [2,4,6,7-3H]- 17ß-estradiol (115 Ci/mmol), [l,2,6,7-3H]-progesterone (103 Ci/mmol), and [17a-methyl-'H]-R5020 (86 had relatively little effect on tubule cell proliferation. The hydrolyzed Premarin exhibited a maximal 2.0-fold cell proliferative response at Ci/mmol) were obtained from New England Nuclear (Boston, MA). Radioinert 10 mi. Chromatographie grade estradiol, estrone, and progeslerone were purchased The present results provide clear evidence that, in the hamster kidney, from Calbiochem (Behring, ÇA), and all other nonlabelcd steroids were obtained either from Sigma Chemical Co. (St. Louis, MO) or Steraloids the degree of carcinogenicity of a given estrogen correlates with its ability (Wilton, NH). Deoxoestrone was prepared by Dr. Luke K. T. Lam (LKT to induce proximal tubule cell proliferation in vitro. Therefore, the ability Laboratories, Minneapolis, MN). Indenestrol B and indanestrol were gener of estrogen to enhance tubule cell proliferation is a more accurate indi ously provided by Dr. Manfred Metzler (University of Kaiserslautern, Kaiser cator of its carcinogenicity in this system than either the estrogen-respon slautern, Germany); MOX3 (llß-methoxyethinylestradiol) by Dr. J. P. sive end points used or the amount of catechol metabolites generated in Raynaud (Roussel UCLAF, Paris, France); and 16a-hydroxyestrone by Dr. this tissue as reported earlier. Jack Fishman (IVAX Corp., Miami, FL). All estrogens investigated exhibited purities of at least 95% as shown by HPLC analyses by using a Waters model 840 liquid Chromatograph equipped with a Waters 490 programmable multi- Received 4/17/95; accepted 7/27/95. wavelength detector. Estrogen samples (10 fig), dissolved in tetrahydrofuran. The costs of publication of this article were defrayed in part by the payment of page were injected and eluted on two tandem octadecyl (Cls) columns, 0.46 x 25 cm charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. (IBM, Wallingford. CT), by using 29% acetonitrile in water isocratically at a 1This investigation was supported by National Cancer Institute, NIH Grants CA58030 column temperature of 35°Cand at a flow rate of 3 ml/min. Conjugated and CA22008 and a Kansas Masonic Oncology Research Center grant. estrogens were hydrolyzed from Premarin (Wyeth-Ayerst, Philadelphia. PA) 2 To whom requests for reprints should be addressed, at Division of Etiology and Prevention of Hormonal Cancers. University of Kansas Cancer Center, Robinson Suite 5008, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS ' The abbreviations used are: MOX, Moxestrol; PRL, prolactin; ER, estrogen receptor; 66160-7312. DES, diethylstilbestrol; PR, progesterone receptor; EE, ethinylestradiol. 4347 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1995 American Association for Cancer Research. CARCINOGENIC ACTIVITY OF ESTROGENS AND CELL PROLIFERATION by using sulfatase, type H-l (Sigma), for 5 h under N2 in 0.2 N sodium acetate, [*H(-progesterone or |'H]-R502(), alone or in combination with corre pH 5.0. HPLC separation of the unconjugated estrogens in hydrolyzed Pre- sponding radioinert hormones (100-fold excess). Dcxlran-charcoal treat marin is shown in Fig. 1. The composition of the hydrolyzed Premarin ment was 10 min (20-22). Protein concentrations of the renal tumor and prepared was estrone (42%), equilin (17%), 17a-dihydroequilin (3.4%), 17a- kidney cytosols were determined by the method of Lowry el al. (24). estradiol (2.4%), 8-dihydroestrone (18%), 17ß-dihydroequilin (0.7%), equi- Hamster PRL Bioassay. To determine PRL levels in hamster serum lenin (4.3%), 17a-dihydroequilenin (10%), 17ß-estradiol (1.5%), and 17ß- samples, the Nb, node lymphoma bioassay was used as described previously dihydroequilenin (0.7%). in detail (19, 25). Serum samples were obtained at 9.0 months from each of the Animals and Treatments. Young adult castrated male Syrian golden ham estrogen-treated animals via the inferior vena cava. The Nb2 node rat lym sters, weighing 85-95 g, were purchased from HaríanSprague-Dawley (Indi phoma cells were kindly provided by Dr. R. L. Noble and Dr. C. T. Beer. anapolis, IN). All animals were acclimated 1 week before treatment or use. (University of British Columbia, Vancouver,
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