Jj. Li et al., CARCINOGENIC ACTIVITIES OF VARIOUS STEROIDAL AND NONSTEROIDAL ESTROGENS IN THE HAMSTER-KIDNEY - RELATION TO HORMONAL ACTIVITY AND CELL-PROLIFERATION, Cancer research, 55(19), 1995, pp. 4347-4351
The therapeutic use of estrogens has been associated with an increased
risk of same of the most predominant, as well as less prevalent, canc
ers in women, The estrogen-induced renal tumor is one of the primary a
nimal models to evaluate the carcinogenic properties of estrogens. Cor
relations were made with various estrogens by using parameters of estr
ogenicity end points such as competitive binding, progesterone recepto
r induction, and alterations in prolactin levels; in vitro renal proxi
mal cell proliferation; and in vivo estrogen-induced carcinogenicity.
The most potent estrogens were Moxestrol (MOX), diethylstilbestrol (DE
S), and 17 beta-estradiol, followed by indenestrol B, 16 alpha-hydroxy
estrone, and 11 beta-methoxyestradiol with moderate estrogenic activit
ies, whereas 11 beta-methytestradiol, 17 alpha-estradiol, indanestrol,
and deoxoestrone were all relatively weaker. As expected, hydrolyzed
Premarin (unconjugated estrogens) was strongly estrogenic Of the estro
gens tested, MOX was the most potent carcinogenic estrogen in the hams
ter kidney. Both 16 alpha-hydroxyestrone and 11 beta-methoxyestradiol
induced intermediate tumor incidences with distinctly lower frequencie
s of renal tumor foci compared to the most potent carcinogenic estroge
ns. However, hamsters treated for 9.0 months with 11 beta-methylestrad
iol, 17 alpha-estradiol, deoxoestrone, and indanestrol exhibited no tu
mors. In contrast, treatment with estrone, equilin plus d-equilenin, a
nd 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 v
arying estrogen concentrations (0.01-100 nM). Exposure to MOX resulted
in consistently high renal cell proliferative response over a concent
ration range of 0.1-10 nM. Strongly carcinogenic estrogens such as est
rone had a maximal renal cell proliferation response (2.4-fold above u
ntreated control levels) between 0.1 and 10 nM, DES and 17 beta-estrad
iol responded at 1.0 nM, and 4-hydroxyestradiol responded at 10 nM. In
terestingly, exposure to ethinylestradiol, a potent estrogen, at simil
ar or higher doses as those used for DES and 17 beta-estradiol, yielde
d only a 10% renal tumor incidence and induced only a 1.7-fold increas
e in proximal tubule cell proliferation. In contrast, 17 alpha-estradi
ol, deoxoestrone, indanestrol, and 11 beta-methylestradiol, all weakly
estrogenic and noncarcinogenic agents, had relatively little effect o
n tubule cell proliferation. The hydrolyzed Premarin exhibited a maxim
al 2.0-fold cell proliferative response at 10 nM. The present results
provide clear evidence that, in the hamster kidney, the degree of carc
inogenicity 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 indi
cator of its carcinogenicity in this system than either the estrogen-r
esponsive end points used or the amount of catechol metabolites genera
ted in this tissue as reported earlier.