Previous reports indicate that flutamide withdrawal is associated with PSA declines and tumor shrinkage in selected patients with 'hormone-refractory' prostate cancer. Though the mechanisms underlying this effect are not clear, investigators have hypothesized that these effects are mediated by mutant androgen receptors recognizing hydroxy-flutamide as an androgenic agonist. Such receptors have been well described in the human prostate cancer cell line LNCaP. Despite the finding that the androgen receptor of LNCaP aberrantly recognizes a variety of steroids, including estrogen and progesterone, as androgenic agonists, there are no studies which examine the effect of estrogen antagonists and progesterone antagonist on baseline and androgen-stimulated LNCaP growth. In this report, LNCaP cells were cultured in phenol red-free media using charcoal-stripped sera. As previously reported, flutamide enhanced LNCaP growth and bicalutamide inhibited androgen-stimulated LNCaP proliferation. Neither tamoxifen nor RU486 influenced LNCaP growth (either in the presence or absence of exogenous androgens). From these data we conclude that antagonists of estrogen and progesterone action have no anti-proliferative effect on LNCaP cells and that the mutant androgen receptor expressed in these cells is quite restrictive in the recognition of compounds with antagonistic activity. The clinical implications of these findings are discussed.

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