Disease relevance of NSC722665

• Structural basis for antagonism and resistance of bicalutamide in prostate cancer [1].
• RESULTS: Gynecomastia developed in 73% of patients in the bicalutamide group, 10% of patients in the bicalutamide-tamoxifen group, and 51% of patients in the bicalutamide-anastrozole group (P < .001); breast pain developed in 39%, 6%, and 27% of patients, respectively (P = .006) [2].
• After disease progression, patients treated with bicalutamide were assigned to castration [3].
• DHEA bound to AR with a Ki of 1 microM, which was associated with AR transcriptional antagonism on both the mouse mammary tumor virus and prostate-specific antigen promoters, much like the effects of bicalutamide [4].
• Interstitial pneumonitis following bicalutamide treatment for prostate cancer [5].

Psychiatry related information on NSC722665

• Fewer patients in the bicalutamide group complained of loss of libido (P =. 01) and of erectile dysfunction (P =.002) [3].
• Side effects such as hot flushes, loss of libido, lethargy and decreased bone mineral density have recently stimulated more interest in the use of non-steroidal anti-androgens such as bicalutamide (Casodex, AstraZeneca) in locally advanced disease [6].

High impact information on NSC722665

• Our earlier report suggested that androst-5-ene-3beta,7beta-diol (Delta(5)-androstenediol or Adiol) is a natural hormone with androgenic activity and that two potent antiandrogens, hydroxyflutamide (Eulexin) and bicalutamide (Casodex), fail to block completely the Adiol-induced androgen receptor (AR) transactivation in prostate cancer cells [7].
• Antiandrogen bicalutamide promotes tumor growth in a novel androgen-dependent prostate cancer xenograft model derived from a bicalutamide-treated patient [8].
• Baseline PSA level decreased by > or = 50% in 97%, 97%, and 83% of patients in the bicalutamide, bicalutamide-tamoxifen, and bicalutamide-anastrozole groups, respectively (P = .07); and adverse events were reported in 37%, 35%, and 69% of patients, respectively (P = .004) [2].
• CONCLUSION: Anastrozole did not significantly reduce the incidence of bicalutamide-induced gynecomastia and breast pain [2].
• For the first time, we show the agonistic effect of bicalutamide to a xenograft with clinically induced AR mutation [8].

Chemical compound and disease context of NSC722665

• Antiandrogens such as Casodex (Bicalutamide) are designed to treat advance stage prostate cancer by interfering with androgen receptor-mediated cell survival and by initiating cell death [9].
• CONCLUSION: In men with prostate cancer, bicalutamide monotherapy increases bone mineral density, lessens fat accumulation, and has fewer bothersome side effects than treatment with a gonadotropin-releasing hormone agonist [10].
• Additive antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), and the nonsteroidal antiandrogen, bicalutamide (Casodex), in prostate cancer cells in vitro [11].
• PURPOSE: We investigated the role of tamoxifen and radiotherapy (RT) for the prevention and treatment of gynecomastia and breast pain during adjuvant bicalutamide monotherapy after radical prostatectomy (RP) in patients with prostate cancer [12].
• PURPOSE: The antiproliferative effects of pharmacological agents used for androgen ablative therapy in prostate cancer, including goserelin, bicalutamide and cyproterone acetate (Fluka Chemie, Buchs, Switzerland), were tested in vitro [13].

Biological context of NSC722665

• Less is known about the effects of bicalutamide monotherapy on bone mineral density and body composition [10].
• Bicalutamide stimulated LNCaP-cxD cell growth and increased prostate-specific antigen secretion from LNCaP-cxD cells both in vitro and in vivo [14].
• R1881-induced IGF-IR up-regulation was partially inhibited by the AR antagonist Casodex (bicalutamide) [15].
• Hormone-stimulated phosphorylation of AKT requires AR since incubation with the anti-androgen bicalutamide completely abolishes the androgen-stimulated AKT phosphorylation [16].
• The present study was designed to investigate the regulation of AR expression and function by OSM, as well as the efficacy of the nonsteroidal antiandrogens hydroxyflutamide and bicalutamide in the inhibition of AR-mediated signal transduction [17].

Anatomical context of NSC722665

• Stimulation of FAS activity is inhibited by the antiandrogen Casodex (bicalutamide) and is absent in the androgen receptor-negative cell lines PC-3 and DU-145 [18].
• Bicalutamide in the treatment of advanced prostatic carcinoma: a phase II noncomparative multicenter trial evaluating safety, efficacy and long-term endocrine effects of monotherapy [19].
• The transactivation assay demonstrated that, analogous to bicalutamide, estramustine could not induce luciferase activity in either w-pAR0 or m-pARL transfected HeLa cells [20].
• Effects of long-term treatment with the anti-androgen bicalutamide on human testis: an ultrastructural and morphometric study [21].
• In mature male rats, daily oral doses of bicalutamide produce a dose-related reduction in weights of the ventral prostate glands and seminal vesicles: in this test, bicalutamide is around five times as potent as flutamide [22].

Associations of NSC722665 with other chemical compounds

• After progression on bicalutamide monotherapy, one third of patients with androgen-dependent progression responded to medical castration with a GnRH analog [23].
• Patients with flutamide-stimulated AR mutations responded to subsequent treatment with bicalutamide, an AR antagonist that blocks the mutant ARs [24].
• Recently, our laboratory discovered selective androgen receptor modulators, which structurally resemble the nonsteroidal AR antagonists bicalutamide and hydroxyflutamide but act as agonists for the androgen receptor in a tissue-selective manner [25].
• To obtain insight into the mechanism by which antagonists block AR function in living cells, we studied nuclear mobility and localization of green fluorescent protein (GFP)-tagged AR in the presence of either the agonist R1881 or the antagonists bicalutamide and hydroxyflutamide [26].
• We found that mifepristone could induce a strong interaction between AR and corepressors nuclear receptor corepressor and silencing mediator for retinoid and thyroid hormone receptors in both transactivation and two-hybrid assays to a greater degree than hydroxyflutamide, cyproterone acetate, and bicalutamide [27].

Gene context of NSC722665

• Because antiandrogen, bicalutamide, blocked adiol activity in LNCaP cells, it was suggested that adiol effect was mediated through AR [28].
• This repression was inhibited by the antiandrogen bicalutamide, suggesting that androgens negatively regulate WNT11 expression through the androgen receptor [29].
• Similarly to androgen-independent PCa in patients, the relapsed xenografts and cell line expressed AR and were resistant to treatment with bicalutamide [30].
• However, using midazolam as a specific CYP3A4 marker, no clinically relevant inhibition is observed in vivo with bicalutamide 150mg [31].
• Moreover, in AR-transfected DU145 cells, chronic treatment with bicalutamide increased EGFR expression to levels similar to androgen-independent DU145 cells [11].
• A logistic multiple regression analysis revealed that a switch of p-Akt control from a PTEN/EGFR- to Her2-after bicalutamide treatment was possible [32].

Analytical, diagnostic and therapeutic context of NSC722665

• PATIENTS AND METHODS: Individual data from 2,161 advanced PCa patients treated in studies comparing bicalutamide to castration were used in a meta-analytic approach to surrogate end-point validation [33].
• Prophylactic breast irradiation with a single dose of electron beam radiotherapy (10 Gy) significantly reduces the incidence of bicalutamide-induced gynecomastia [34].
• In the groups treated with radiation therapy or radical prostatectomy, regardless of the addition of bicalutamide, the incidence of positive bone scans was low (0.2% to 1.4%) at prostate specific antigen levels less than 5 ng/ml [35].
• These data suggest that different AR variants are developed and selected for during various types of hormonal treatments, and also, that CAB achieved by orchiectomy and bicalutamide does not act as a selective force for AR amplification [36].
• Clinical trials are currently in progress to further evaluate bicalutamide as monotherapy in patients with advanced stages of disease and as adjuvant or first-line therapy in patients with early-stage disease [37].

References