Idoxifene is a novel selective
estrogen (E2) receptor (ER) modulator that is currently in clinical development for the treatment of
breast cancer. Compared to
tamoxifen,
idoxifene is metabolically more stable, with a higher relative binding affinity for the ER and reduced agonist activity on breast and uterine cells.
Idoxifene also inhibits
calmodulin, a
calcium-binding protein that is involved in cell signal transduction pathways. In this study, the abilities of
idoxifene and
tamoxifen to antagonize E2-dependent MCF-7 xenograft growth in oophorectomized athymic mice were compared. The basis for
idoxifene's antitumor activity was examined by comparing the effectiveness of the clinically used transisomer (referred to here as
idoxifene) with its cis-isomer, which has a 50-fold lower relative binding affinity for ER than
idoxifene but similar
calmodulin-inhibitory activity. Changes in
tumor cell proliferation, apoptosis, and ER-dependent
protein expression were studied. Both
idoxifene and
tamoxifen significantly inhibited E2-dependent
tumor growth, whereas cis-
idoxifene had little effect. Withdrawal of E2 support induced significant
tumor regression due to impaired cell proliferation (Ki-67 score, 9 versus 51% compared to E2 controls) and induction of apoptosis (3.6 versus 0.9% compared to E2 controls). Both anti-E2s inhibited cell proliferation and caused a significant 3-fold induction of apoptosis in E2 supported
tumors after 1 week, which was maintained for 3 months with
idoxifene (3.1 versus 0.48% compared to E2 controls) but decreased back to baseline in
tumors treated with
tamoxifen (0.69%). In contrast, cis-
idoxifene had no effect on either cell proliferation or apoptosis. Both
tamoxifen and
idoxifene initially induced ER expression, whereas prolonged
therapy with
tamoxifen significantly reduced
progesterone receptor levels. In conclusion,
idoxifene resulted in similar inhibition of E2-dependent MCF-7 xenograft growth compared with
tamoxifen, an effect that is mediated via ER rather than through
calmodulin. Sustained induction of apoptosis may contribute to prolonged antagonism of E2-dependent growth, and it occurred to a greater extent following 3 months of
idoxifene, compared to
tamoxifen.