This study analyzed the effectiveness of a nonsteroidal
antiestrogen, cis-(3-[p-(1,2,3,4-tetrahydro-6-methoxy-2-phenyl-1-naphthyl)phenoxy]-
1,2-propanediol (
U 23,469) previously shown to be potent in antagonizing
estrogen-induced uterine growth, in preventing the development of 7,12-dimethylbenz(a)
anthracene (DMBA)-induced rat mammary
tumors and in eliciting the regression of established
tumors; the study also attempts to elucidate the mechanisms of the
tumor antagonism of
U 23,469. Virgin female Sprague-Dawley rats that receive DMBA at 47 to 50 days of age and then receive
U 23,469 (250 micrograms s.c. in 0.15 M NaCl daily) have a greatly reduced number of mammary
tumors and a markedly decreased
tumor area. Treatment with
U 23,469 for increasing time periods (3, 6, or 12 weeks) beginning 2 weeks after DMBA results in a progressive delay in onset of
tumor appearance.
U 23,469 treatment beginning 1 week after DMBA or given prior to DMBA is even more effective. The time course of
tumor regression (3 months after DMBA) by
U 23,469 or
ovariectomy is similar, with 50% regression in ca. 2 weeks, and both elicit regression of almost all
tumors (greater than 90%). After
ovariectomy, cytosol
progesterone receptor levels are greatly diminished in
tumors and uteri, while cytosol
estrogen receptor (ER) levels are high; in both tissues little (ca. one-third) of ER is in the nucleus. During
U 23,469 treatment, cytosol ER content is very low in regressing
tumor and uterus and over 90% of ER is in the nucleus; cytosol
progesterone receptor is slightly depressed in the uterus but is at the untreated level in mammary
tumor. These receptor studies suggest that the effectiveness of this
antiestrogen in antagonizing mammary
tumor development and growth may reside in its ability markedly to perturb the distribution of ER, maintaining over 90% of ER in the nucleus with concomitant low levels of cytoplasmic ER, a situation that may render the mammary tissue insensitive to the animal's own endogenous
estrogens.