RT Journal Article
SR Electronic
T1 Carcinogenic Activities of Various Steroidal and Nonsteroidal Estrogens in the Hamster Kidney: Relation to Hormonal Activity and Cell Proliferation
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 4347
OP 4351
VO 55
IS 19
A1 Li, Jonathan J.
A1 Li, Sara Antonia
A1 Oberley, Terry D.
A1 Parsons, Jonathan A.
YR 1995
UL http://cancerres.aacrjournals.org/content/55/19/4347.abstract
AB The therapeutic use of estrogens has been associated with an increased risk of some of the most predominant, as well as less prevalent, cancers in women. The estrogen-induced renal tumor is one the primary animal models to evaluate the carcinogenic properties of estrogens. Correlations were made with various estrogens by using parameters of estrogenicity end points such as competitive binding, progesterone receptor induction, and alterations in prolactin levels; in vitro renal proximal cell proliferation; and in vivo estrogen-induced carcinogenicity. The most potent estrogens were Moxestrol (MOX), diethylstilbestrol (DES), and 17β-estradiol, followed by indenestrol B, 16α-hydroxyestrone, and 11β-methoxyestradiol with moderate estrogenic activities, whereas 11β-methylestradiol, 17α-estradiol, indanestrol, and deoxoestrone were all relatively weaker. As expected, hydrolyzed Premarin (unconjugated estrogens) was strongly estrogenic. Of the estrogens tested, MOX was the most potent carcinogenic estrogen in the hamster kidney. Both 16α-hydroxyestrone and 11β-methoxyestradiol induced intermediate tumor incidences with distinctly lower frequencies of renal tumor foci compared to the most potent carcinogenic estrogens. However, hamsters treated for 9.0 months with 11β-methylestradiol, 17α-estradiol, deoxoestrone, and indanestrol exhibited no tumors. In contrast, treatment with estrone, equilin plus d-equilenin, and hydrolyzed Premarin for the same time period resulted in 100% renal tumor incidences and numerous tumor foci. Cell proliferation studies of cultured hamster kidney proximal tubule cells were carried out at varying estrogen concentrations (0.01-100 nm). Exposure to MOX resulted in consistently high renal cell proliferative response over a concentration range of 0.1–10 nm. Strongly carcinogenic estrogens such as estrone had a maximal renal cell proliferation response (2.4-fold above untreated control levels) between 0.1 and 10 nm, DES and 17β-estradiol responded at 1.0 nm, and 4-hydroxyestradiol responded at 10 nm. Interestingly, exposure to ethinylestradiol, a potent estrogen, at similar or higher doses as those used for DES and 17β-estradiol, yielded only a 10% renal tumor incidence and induced only a 1.7-fold increase in proximal tubule cell proliferation. In contrast, 17α-estradiol, deoxoestrone, indanestrol, and 11β-methylestradiol, all weakly estrogenic and noncarcinogenic agents, had relatively little effect on tubule cell proliferation. The hydrolyzed Premarin exhibited a maximal 2.0-fold cell proliferative response at 10 nm. The present results provide clear evidence that, in the hamster kidney, the degree of carcinogenicity of a given estrogen correlates with its ability to induce proximal tubule cell proliferation in vitro. Therefore, the ability of estrogen to enhance tubule cell proliferation is a more accurate indicator of its carcinogenicity in this system than either the estrogen-responsive end points used or the amount of catechol metabolites generated in this tissue as reported earlier. ©1995 American Association for Cancer Research.