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- Steroid derivatives as pure antagonists of the androgen receptor. [Journal Article]
- J Steroid Biochem Mol Biol 2012 Oct; 132(1-2):93-104.
While the androgens of testicular origin (representing about 50% of total androgens in men over 50 years) can be completely eliminated by surgical or medical castration with GnRH (gonadotropin-releasing hormone) agonists or antagonists, the antiandrogens currently available as blockers of androgen binding to the androgen receptor (AR), namely bicalutamide (BICA), flutamide (FLU) and nilutamide have too weak affinity to completely neutralize the other 50% of androgens made locally from dehydroepiandrosterone (DHEA) in the prostate cancer tissue by the mechanisms of intracrinology.Series of steroid derivatives having pure and potent antagonistic activity on the human and rodent AR were synthesized. Assays of AR binding and activity in carcinoma mouse Shionogi and human LNCaP cells as well as in vivo bioavailability measurements and in vivo prostate weight assays in the rat were used.The chosen lead steroidal compound, namely EM-5854, has a 3.7-fold higher affinity than BICA for the human AR while EM-5855, an important metabolite of EM-5854, has a 94-fold higher affinity for the human AR compared to BICA. EM-5854 and EM-5855 are 14 times more potent than BICA in inhibiting androgen (R1881)-stimulated prostatic specific antigen (PSA) secretion in human prostatic carcinoma LNCaP cells in vitro. MDV3100 has a potency comparable to bicalutamide in these assays. Depending upon the oral formulation, EM-5854 is 5- to 10-times more potent than BICA to inhibit dihydrotestosterone (DHT)-stimulated ventral prostatic weight in vivo in the rat while MDV3100 has lower activity than BICA in this in vivo model. These data are supported by respective 40-fold and 105-fold higher potencies of EM-5854 and EM-5855 compared to BICA to inhibit cell proliferation in the androgen-sensitive Shionogi carcinoma cell model.Although the present preclinical results data need evaluation in clinical trials in men, combination of the data obtained in vitro in human LNCaP cells as indicator of potency in the human prostate and the data on metabolism evaluated in vivo on ventral prostate weight in the rat, could suggest the possibility of a 70- to 140-fold higher potency of EM-5854 compared to bicalutamide (Casodex) for the treatment of prostate cancer in men.
- Nilutamide. [Journal Article]
- Acta Crystallogr Sect E Struct Rep Online 2012 Mar 1; 68(Pt 3):o591.
THE CRYSTAL STRUCTURE OF NILUTAMIDE [SYSTEMATIC NAME: 5,5-dimethyl-3-[4-nitro-3-(trifluoro-meth-yl)phen-yl]imidazolidine-2,4-dione], C(12)H(10)F(3)N(3)O(4), was determined at 150 K. The dihedral angle between the mean planes through the imidazoline [maximum deviation = 0.0396 (14) Å] and benzene rings is 51.49 (5)°. The mol-ecule exhibits inter-molecular hydrogen bonding via N-H⋯O inter-actions, resulting in the formation of chains parallel to the c axis.
- [Monotherapy versus combined androgen blockade for advanced/metastatic prostate cancer]. [English Abstract, Journal Article]
- Gan To Kagaku Ryoho 2011 Dec; 38(13):2553-7.
In advanced/metastatic prostate cancer, a standard treatment is androgen deprivation therapy, either by surgical castration/LH-RH agonist monotherapy or by combined androgen blockade (CAB) with an antiandrogen. Clinical improvement and survival after CAB with an antiandrogen (instead of monotherapy) has been investigated for 20 years in many randomized clinical trials conducted primarily in Europe and America. However, there were both positive and negative results regarding the efficacy of CAB therapy. Therefore, CAB has neither been recommended as, nor has it become, a common therapy. But, in 2000, a meta-analysis-conducted Prostate Cancer Trialists Collaborative Group (PCTCG)showed the survival benefits of CAB with nonsteroidal antiandrogen (nilutamide and flutamide). Moreover, the J-Cap phase III trial in Japan suggested that CAB with bicalutamide significantly prolongs survival, which has led to the placement of CAB as the treatment of choice for advanced/metastatic prostate cancer. Neverthless, the benefit of CAB compared to monotherapy remains controversial because of the many issues involving survival, safety profiles, QOL, and cost-effectiveness. In this article, we discuss the feasibility of CAB for advanced/metastatic prostate cancer by reviewing the results of RCT, and introduce novel treatment modalities involving androgen and the androgen receptor, which are still under development.
- Anti-androgen effects of cypermethrin on the amino- and carboxyl-terminal interaction of the androgen receptor. [Journal Article, Research Support, Non-U.S. Gov't]
- Toxicology 2012 Feb 26; 292(2-3):99-104.
The pyrethroid insecticide, cypermethrin has been demonstrated to be an environmental anti-androgen in the androgen receptor (AR) reporter gene assay. The amino- and carboxyl-terminal (N/C) interaction is required for transcription potential of the AR. In order to characterize the anti-androgen effects of cypermethrin involved in the N/C interaction of AR, the mammalian two-hybrid assay has been developed in the study. The fusion vectors pVP16-ARNTD, pM-ARLBD and the pG5CAT Reporter Vector were cotransfected into the CV-1 cells. The assay displayed appropriate response to the potent, classical AR agonist 5α-dihydrotestosterone (DHT) and known AR antagonist nilutamide. The N/C interaction was induced by DHT from 10(-11)M to 10(-5)M in a dose-dependent manner. Nilutamide did not activate N/C interaction, while inhibited DHT-induced AR N/C interaction at the concentrations from 10(-7)M to 10(-5)M. Treatment of CV-1 cells with cypermethrin alone did not activate the reporter CAT. Cypermethrin significantly decreased the DHT-induced reporter CAT expression at the higher concentration of 10(-5)M. The mammalian two-hybrid assay provides a promising tool both for defining mechanism involved in AR N/C interaction of EDCs and for screening of chemicals with androgen agonistic and antagonistic activities. Cypermethrin exhibits inhibitory effects on the DHT-induced AR N/C interaction, while the potency is weaker than that of nilutamide.
- Androgen receptor-mediated regulation of the anti-atherogenic enzyme CYP27A1 involves the JNK/c-jun pathway. [Journal Article, Research Support, Non-U.S. Gov't]
- Arch Biochem Biophys 2011 Feb 15; 506(2):236-41.
CYP27A1, an enzyme with several important roles in cholesterol homeostasis and vitamin D₃ metabolism, has been ascribed anti-atherogenic properties. This study addresses an important problem regarding how this enzyme, involved in cholesterol metabolism in the liver and peripheral tissues, is regulated. Our results identify the human CYP27A1 gene as a new target for the JNK/c-jun pathway. Initial experiments showed that an inhibitor of c-Jun N-terminal kinase (JNK) downregulated basal CYP27A1 promoter activity whereas overexpression of JNK slightly enhanced promoter activity. Androgen receptor (AR)-mediated upregulation of mRNA levels and endogenous enzyme activity was recently reported. In the present study, the AR antagonist nilutamide blocked the androgen induction of CYP27A1. The present data revealed that inhibition of the JNK/c-jun pathway abolishes the AR-mediated effect on CYP27A1 transcription and enzyme activity, whereas overexpression of JNK markedly increased androgenic upregulation of CYP27A1. In conclusion, the current results indicate involvement of the JNK/c-jun pathway in AR-mediated upregulation of human CYP27A1. The link to JNK signaling is interesting since inflammatory processes may upregulate CYP27A1 to clear cholesterol from peripheral tissues.
- Combined androgen blockade for prostate cancer: review of efficacy, safety and cost-effectiveness. [Journal Article, Review]
- Cancer Sci 2011 Jan; 102(1):51-6.
A standard treatment for advanced prostate cancer is androgen deprivation by surgical or medical castration. In theory, however, combined androgen blockade (CAB) with an antiandrogen plus castration should be more effective because castration alone does not completely eliminate androgens in the prostate. Therefore, a number of randomized clinical trials (RCT) were conducted in the 1990s to investigate the efficacy of CAB with an antiandrogen (nilutamide or flutamide) plus castration; however, there were both positive and negative results for the efficacy of CAB. The lack of data on safety, quality of life (QOL) and cost-effectiveness has been a hindrance to the adoption of CAB for the treatment of prostate cancer. Nevertheless, discussion on CAB for the treatment of prostate cancer has continued for over 20 years, which suggests that there remains some hope for this regimen. In the 2000s, clinical research on CAB with the antiandrogen bicalutamide commenced. CAB using this new antiandrogen was found to prolong overall survival (OS) in patients with prostate cancer, with favorable safety profiles and cost-effectiveness, without deteriorating QOL. In this article, we discuss the feasibility of CAB with bicalutamide for the treatment of prostate cancer by reviewing the theoretical background of CAB and then the results of RCT conducted in the 1990s when the usefulness of CAB was assessed.
- Drug safety is a barrier to the discovery and development of new androgen receptor antagonists. [Journal Article]
- Prostate 2011 Apr; 71(5):480-8.
Androgen receptor (AR) antagonists are part of the standard of care for prostate cancer. Despite the almost inevitable development of resistance in prostate tumors to AR antagonists, no new AR antagonists have been approved for over a decade. Treatment failure is due in part to mutations that increase activity of AR in response to lower ligand concentrations as well as to mutations that result in AR response to a broader range of ligands. The failure to discover new AR antagonists has occurred in the face of continued research; to enable progress, a clear understanding of the reasons for failure is required.Non-clinical drug safety studies and safety pharmacology assays were performed on previously approved AR antagonists (bicalutamide, flutamide, nilutamide), next generation antagonists in clinical testing (MDV3100, BMS-641988), and a pre-clinical drug candidate (BMS-501949). In addition, non-clinical studies with AR mutant mice, and EEG recordings in rats were performed. Non-clinical findings are compared to disclosures of clinical trial results.As a drug class, AR antagonists cause seizure in animals by an off-target mechanism and are found in vitro to inhibit GABA-A currents. Clinical trials of candidate next generation AR antagonists identify seizure as a clinical safety risk.Non-clinical drug safety profiles of the AR antagonist drug class create a significant barrier to the identification of next generation AR antagonists. GABA-A inhibition is a common off-target activity of approved and next generation AR antagonists potentially explaining some side effects and safety hazards of this class of drugs.
- Words of wisdom. Re: Does oral antiandrogen use before leuteinizing hormone-releasing therapy in patients with metastatic prostate cancer prevent clinical consequences of a testosterone flare? Oh WK, Landrum MB, Lamont EB, et al. Urology 2010;75:642-7. [Comment, Journal Article]
- Eur Urol 2010 Aug; 58(2):314-5.
Oh et al report their experience with 1566 metastatic prostate cancer patients treated with luteinising hormone-releasing hormone (LHRH) agonists in the area of Boston, Massachusetts, USA. Of these patients, 79.5% were given antiandrogens (bicalutamide, flutamide, or nilutamide) before the first LHRH agonist dose. The remaining patients (20.5%) did not receive antiandrogens. In all patients, complications appearing within 30 d and attributable to a flare phenomenon (fractures, spinal cord compression, bladder outlet obstruction, exacerbation of pain) were assessed retrospectively. Such complications were extremely rare (<1%) in both groups. There was no difference whether or not antiandrogens were administered. The timing of antiandrogen prescription(0-6 vs > or =7 d before starting the LHRH analogues) made no difference.The authors concluded that no evidence supports a generalised use of antiandrogens in addition to the LHRH agonists. The risks of antiandrogen therapy (hepatic,gastrointestinal, ocular, and pulmonary complications)may counterbalance the benefits of the combined therapy,which is much more expensive.
- Activity of antiandrogens against juvenile and adult Schistosoma mansoni in mice. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't]
- J Antimicrob Chemother 2010 Sep; 65(9):1991-5.
The antischistosomal properties of the marketed antiandrogens bicalutamide, flutamide, nilutamide and cyproterone acetate were studied both in vivo and in vitro.Schistosoma mansoni-infected mice were treated orally with 50-400 mg/kg of the antiandrogens 3 and 7 weeks post-infection. In addition, three drug combinations of nilutamide and praziquantel (200/100, 100/100 and 100/50 mg/kg) were administered to mice harbouring adult S. mansoni. Drug effects were also monitored in vitro following exposure to antiandrogen concentrations of 1, 10 and 100 microg/mL.Low total worm burden reductions (5%-37%) and low to moderate female worm burden reductions (13%-75%) were achieved with the antiandrogens in the S. mansoni juvenile infection model. While flutamide and cyproterone acetate lacked activity against adult S. mansoni in vivo, low to moderate total and female worm burden reductions (0%-47%) were observed with bicalutamide. The highest total and female worm burden reductions (85% and 71%, respectively) (P < 0.001) were documented following a single 400 mg/kg dose of nilutamide. Statistically significant total (91%) and female (85%) worm burden reductions were achieved with the combination of nilutamide (200 mg/kg) and praziquantel (100 mg/kg). Schistosomes incubated with 100 microg/mL cyproterone acetate in vitro died after 15 h. Incubation with bicalutamide, nilutamide and flutamide at 100 microg/mL resulted in decreased movement of S. mansoni adults.Our data indicate that the hydantoin derivative nilutamide has interesting antischistosomal properties, confirming previous results of schistosomicidal activities of this drug class.
- Hormonal therapy of prostate cancer. [Journal Article]
- Prog Brain Res 2010.:321-41.
Of all cancers, prostate cancer is the most sensitive to hormones: it is thus very important to take advantage of this unique property and to always use optimal androgen blockade when hormone therapy is the appropriate treatment. A fundamental observation is that the serum testosterone concentration only reflects the amount of testosterone of testicular origin which is released in the blood from which it reaches all tissues. Recent data show, however, that an approximately equal amount of testosterone is made from dehydroepiandrosterone (DHEA) directly in the peripheral tissues, including the prostate, and does not appear in the blood. Consequently, after castration, the 95-97% fall in serum testosterone does not reflect the 40-50% testosterone (testo) and dihydrotestosterone (DHT) made locally in the prostate from DHEA of adrenal origin. In fact, while elimination of testicular androgens by castration alone has never been shown to prolong life in metastatic prostate cancer, combination of castration (surgical or medical with a gonadotropin-releasing hormone (GnRH) agonist) with a pure anti-androgen has been the first treatment shown to prolong life. Most importantly, when applied at the localized stage, the same combined androgen blockade (CAB) can provide long-term control or cure of the disease in more than 90% of cases. Obviously, since prostate cancer usually grows and metastasizes without signs or symptoms, screening with prostate-specific antigen (PSA) is absolutely needed to diagnose prostate cancer at an 'early' stage before metastasis occurs and the cancer becomes non-curable. While the role of androgens was believed to have become non-significant in cancer progressing under any form of androgen blockade, recent data have shown increased expression of the androgen receptor (AR) in treatment-resistant disease with a benefit of further androgen blockade. Since the available anti-androgens have low affinity for AR and cannot block androgen action completely, especially in the presence of increased AR levels, it becomes important to discover more potent and purely antagonistic blockers of AR. The data obtained with compounds under development are promising. While waiting for this (these) new anti-androgen(s), combined treatment with castration and a pure anti-androgen (bicalutamide, flutamide or nilutamide) is the only available and the best scientifically based means of treating prostate cancer by hormone therapy at any stage of the disease with the optimal chance of success and even cure in localized disease.