Disease relevance of Casodex

• Treatment of androgen sensitive, non-metastatic LNCaP human prostate cancer cells with 0-100 microM Casodex or 0-10 ng/ml TNF-alpha induces cell death in 20-60% of the cells by 48 h in a dose-dependent manner [1].
• Re: A prospective, placebo-controlled study of the antiandrogen Casodex as treatment for patients with benign prostatic hyperplasia [2].
• Inclusion was discontinued at 30 patients after report of liver toxicity when Casodex was given long-term at high doses to mice [3].
• In rats bearing Dunning R3327-G prostate carcinomas casodex exerted a strong antitumour effect at the beginning of therapy [4].
• Casodex has the potential to become an important drug for treatment of prostatic diseases [5].

Psychiatry related information on Casodex

• Even if all patients had side effects, mostly mild, Casodex was well tolerated and patient compliance was excellent [3].

High impact information on Casodex

• The antiandrogen Casodex and specific inhibitors of Src and PI3-kinase prevent both hormonal effects, DNA synthesis and cytoskeletal changes [6].
• We solved the x-ray crystal structure of the mutant W741L AR ligand-binding domain bound to R-bicalutamide at 1.8-A resolution [7].
• The antiandrogen Casodex blocked the effect of androgen, implicating the androgen receptor in regulation of ABCA1 expression by androgens [8].
• In contrast, transcription through the PSA P/E promoter, a prototypical AR-dependent promoter directly activated by agonist, was obliterated only by Casodex [9].
• We show that expression of RasN17 in the hormone-refractory C4-2 cell line enhances in vitro sensitivity to the growth-inhibitory action of the antiandrogen Casodex and inhibits anchorage-independent cell growth [10].

Chemical compound and disease context of Casodex

• Flutamide (89) and its derivatives, Casodex (108) and Anandron (114), are highly effective in the treatment of prostate cancer [11].
• Bicalutamide (Casodex) is a competitive androgen receptor antagonist that inactivates androgen-regulated prostate cell growth and function, leading to cell apoptosis and inhibition of prostate cancer growth [12].
• Pure antiandrogen casodex in a dose used in humans for treatment of prostate cancer decreased the weight of seminal vesicles, organ which is highly sensitive to the androgenic effect, increased insignificantly the concentration of LH and of testosterone, but did not have any effect on bone density or mineral content of bone [13].
• A controlled trial of Casodex (bicalutamide) vs. flutamide, each in combination with luteinising hormone-releasing hormone analogue therapy in patients with advanced prostate cancer. Casodex Combination Study Group [14].
• A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer. Casodex Combination Study Group [15].

Biological context of Casodex

• Taken together, these data support the hypothesis that Casodex induces cell death by a pathway that is independent of changes in DeltaPsim and Bcl-2 actions and results in an extended lag phase of cell survival that may promote the induction of an invasive phenotype after treatment [1].
• In contrast, cells treated with Casodex display loss of cell adhesion, but sustained mitochondrial dehydrogenase activity [1].
• Additionally, we demonstrated that R-bicalutamide stimulates transcriptional activation in AR harboring the M895T point mutation [16].
• Microarrays revealed downregulation of eight genes in cells prevented from entering into S phase by Casodex [17].
• Expression of cell-cycle regulatory genes in S phase control cells versus Casodex-treated cells that fail to enter S phase was studied using a microarray containing cDNA probes for 111 cell-cycle specific genes [17].

Anatomical context of Casodex

• Overexpression of Bcl-2 in LNCaP cells attenuates the induction of cell death by TNF-alpha but not Casodex, suggesting that mitochondria depolarization is not required for the induction of cell death by Casodex [1].
• These data, together with known physicochemical properties of Casodex suggest that a blood-brain barrier exists for the drug which results in exclusion of this antiandrogen from central sites of androgen negative feedback and that this accounts for its peripherally selective antihormonal profile [18].
• Androgen receptor localisation and turnover in human prostate epithelium treated with the antiandrogen, casodex [19].
• Androgen receptor (AR) binding assays of rat ventral prostate gland cytosols revealed a relative binding affinity (RBA) for the AR of 0.267 and a k1 of 1.25 x 10(-7) M for Casodex [18].
• We evaluated the endocrine effects of Casodex 150 mg daily given in monotherapy as primary treatment for patients with prostate cancer [20].

Associations of Casodex with other chemical compounds

• The three-dimensional structure demonstrates that the B ring of R-bicalutamide in the W741L mutant is accommodated at the location of the indole ring of Trp-741 in the WT AR bound to dihydrotestosterone [7].
• This activation can be blocked by an anti-androgen drug bicalutamide (Casodex), implicating the involvement of androgen receptor in this process [21].
• Agonist-bound AR was required because the AR antagonists casodex and hydroxyflutamide failed to translocate beta-catenin [22].
• The c-Met expression is also positively controlled by testosterone, which induces a significant increase in its mRNA level that is abolished by an anti-androgen, casodex [23].
• These antiproliferative effects of 1,25-(OH)2D3 and 9-cis RA, alone or in combination, were blocked by the pure AR antagonist, Casodex [24].

Gene context of Casodex

• Like Cdc6, the levels of both cyclins A and B were attenuated in Casodex-treated cells [17].
• The anti-androgen Casodex enhances the growth-inhibitory action of PTEN and this effect is independent of Akt phosphorylation [25].
• RT-PCR based analysis demonstrates that in LNCaP cells Casodex coordinately alters the expression of steady-state level of mRNAs of several matrix metalloproteases and their cognate inhibitors (most notably MMP2 and TIMP1) [26].
• We detect binding of SMRT to hAR when treating with the antiandrogen CPA, but not with the antihormones casodex or hydroxyflutamide [27].
• The anti-androgen Casodex reduced 5alpha-DHT-stimulated cell growth but had no effect on EGF-R mediated LNCaP growth or EGF-stimulated activated MAPK activity [28].

Analytical, diagnostic and therapeutic context of Casodex

• Chemoprevention of rat prostate carcinogenesis by use of finasteride or casodex [29].
• In a comparative trial, bicalutamide (Casodex) was more effective than flutamide (each in combination with an LHRH analogue) in terms of time to treatment failure and produced a significantly lower incidence of diarrhoea [30].
• Bicalutamide (Casodex) 150 mg/day was administered for 12 months from the day of radiotherapy [31].
• The peripheral selectivity of Casodex in the intact male rat was related to the distribution of radiolabelled antiandrogen following intravenous injection [18].
• METHODS: A total of 1,453 patients with either confirmed metastatic disease (M1), or T3/T4 non-metastatic disease with elevated prostate-specific antigen (M0) were recruited into one of two identical, multicentre, randomised studies to compare 'Casodex' 150 mg/day with castration [32].

References