This study shows that the androgen receptor agonistic potency is clearly concealed by the effects of androgen receptor antagonists in a total sediment extract, demonstrating that toxicity screening of total extracts is not enough to evaluate the full in vitro endocrine disrupting potential of a complex chemical mixture, as encountered in the environment. The anti-androgenic compounds were masking the activity of androgenic compounds in the extract with relatively high anti-androgenic potency, equivalent to 200 nmol flutamide equivalents/g dry weight. A two-step serial liquid chromatography fractionation of the extract successfully separated anti-androgenic compounds from androgenic compounds, resulting in a total androgenic potency of 3,820 pmol dihydrotestosterone equivalents/g dry weight. The fractionation simplified the chemical identification analysis of the original complex sample matrix. Seventeen chemical structures were tentatively identified. Polyaromatic hydrocarbons, a technical mixture of nonylphenol and dibutyl phthalate were identified to contribute to the anti-androgenic potency observed in the river sediment sample. With the GC/MS screening method applied here, no compounds with AR agonistic disrupting potencies could be identified. Seventy-one unidentified peaks, which represent potentially new endocrine disrupters, have been added to a database for future investigation.
In order to study resistance to antiandrogens at the AR transactivation level we used a human AR (hAR) reporter assay system. In addition, we utilized an hAR deletion mutant to determine the functional domain responsible for the acquisition of resistance.
Daily subcutaneous administration of 50 micrograms of the luteinizing hormone-releasing hormone (LHRH) agonist [D-Trp6]LHRH ethylamide in adult dogs causes a transient increase in the serum testosterone (T) concentration which reaches a maximum at 200% above control on days 2-4 of treatment and progressively decreases to 7% of the pretreatment value on day 21, the last time interval studied. After a transient increase, the concentration of serum bioactive luteinizing hormone (LH) was progressively decreased on days 11 and 19, thus suggesting that in analogy with human findings, the loss of LH bioactivity is responsible for the inhibition of testicular steroidogenesis induced in the dog by LHRH agonists. Of major significance is the finding that the changes in serum T levels observed during the first 3 weeks of treatment, as well as the complete inhibition of the intratesticular concentration of sex steroids observed at the end of this period of treatment with the LHRH agonist were not affected by simultaneous administration of flutamide (125 mg per os every 8 h). Such findings indicate that at the dose used, the LHRH agonist is in full control of gonadotropin secretion, thus completely overcoming feedback influences. Since the administration of the antiandrogen flutamide does not decrease the efficacy of the LHRH agonist as blocker of testicular androgen biosynthesis, the present data support the use of a pure antiandrogen in order to neutralize the effect of the transient rise in testicular androgen secretion which always accompanies the first days of treatment with LHRH agonists in patients with advanced prostate cancer.
The present study is the second in a series aiming at a systematic inventory of specific toxic effects of oils. By employing a recombinant yeast stably transfected with human estrogen receptor-alpha (ERalpha) or -beta (ERbeta) or androgen receptor (AR) and expressing yeast enhanced green fluorescent protein, the (anti-)estrogenicity and (anti-)androgenicity of 11 crude oils and refined products were studied. None of the oils tested had significant estrogenic effects in the ERalpha assay or androgenic effects in the AR assay. However, all oils were capable of inducing estrogenic responses in the ERbeta assay, with several responses being above even the maximal response of the standard 17beta-estradiol (E2). Based on the lowest effect concentrations, the potencies of oils in all the assays were between four and seven orders of magnitude lower than those of the standards E2 or testosterone (T). The potencies of the actual individual petrochemical agonists may, however, be relatively high, considering the complex composition of oils. Additive effects, antagonistic effects, and a synergistic effect were measured in the assays upon coexposure to a fixed concentration of standard (E2 or T) and increasing concentrations of oils. To investigate whether the observed effects were receptor-mediated, coexposures to the synthetic inhibitors ICI 182,780 (ERbeta assay) or flutamide (AR assay), a fixed concentration of standard, and various concentrations of oils were performed. The results suggested that the androgenic effects were receptor mediated, whereas the estrogenic effects may be only partially mediated via the receptor. The present study indicates that oils contain compounds with possible endocrine-disrupting potential, some of them acting via the hormone receptors.
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It has been reported that blocking of testosterone production inhibits bladder carcinogenesis in various animal models. We investigated how testosterone acts on rat bladder carcinogenesis using an antiandrogen, flutamide, and a 5 alpha-reductase inhibitor, finasteride.
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The present study describes the role of the ubiquitin ligase Siah-2 and corepressor N-CoR in controlling androgen receptor (AR) and estrogen receptors (ERα and ERβ) signaling in an appropriate animal model (Fischer 344 female rats) of non-muscle invasive bladder cancer (NMIBC), especially under conditions of anti-androgen therapy with flutamide. Furthermore, this study describes the mechanisms of a promising therapeutic alternative for NMIBC based on Protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride (P-MAPA) intravesical immunotherapy combined with flutamide, involving the interaction among steroid hormone receptors, their regulators and Toll-like receptors (TLRs). Our results demonstrated that increased Siah-2 and AR protein levels and decreased N-CoR, cytochrome P450 (CYP450) and estrogen receptors levels played a critical role in the urothelial carcinogenesis, probably leading to escape of urothelial cancer cells from immune system attack. P-MAPA immunotherapy led to distinct activation of innate immune system TLRs 2 and 4-mediated, resulting in increase of interferon signaling pathway, which was more effective in recovering the immunosuppressive tumor immune microenvironment and in recovering the bladder histology features than BCG (Bacillus Calmette-Guerin) treatments. The AR blockade therapy was important in the modulating of downstream molecules of TLR2 and TLR4 signaling pathway, decreasing the inflammatory cytokines signaling and enhancing the interferon signaling pathway when associated with P-MAPA. Taken together, the data obtained suggest that interferon signaling pathway activation and targeting AR and Siah-2 signals by P-MAPA intravesical immunotherapy alone and/ or in combination with AR blockade may provide novel therapeutic approaches for NMIBC.
The aim of our study is to elucidate whether experimental arterial thrombosis is regulated by physiological doses of androgen and its receptor via modulation of platelet activation.
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We present a systems biology analysis of rat primary hepatocytes response after exposure to 10 μM and 100 μM flutamide in liver microfluidic biochips. We coupled an in vitro pharmacokinetic (PK) model of flutamide to a system biology model of its reactive oxygen species (ROS) production and scavenging by the Nrf2 regulated glutathione production. The PK model was calibrated using data on flutamide kinetics, hydroxyflutamide and glutathione conjugates formation in microfluidic conditions. The parameters of Nrf2-related gene activities and the subsequent glutathione depletion were calibrated using microarray data from our microfluidic experiments and literature information. Following a 10 μM flutamide exposure, the model predicted a recovery time to baseline levels of glutathione (GSH) and ROS in agreement with our experimental observations. At 100 μM, the model predicted that metabolism saturation led to an important accumulation of flutamide in cells, a high ROS production and complete GSH depletion. The high levels of ROS predicted were consistent with the necrotic switch observed by transcriptomics, and the high cell mortality we had experimentally observed. The model predicted a transition between recoverable GSH depletion and deep GSH depletion at about 12.5 μM of flutamide (single perfusion exposure). Our work shows that in vitro biochip experiments can provide supporting information for complex in silico modeling including data from extra cellular and intra cellular levels. We believe that this approach can be an efficient strategy for a global integrated methodology in predictive toxicology.
In a prospective randomised study the effect of flutamide 750 mg daily was compared with that of stilboestrol 3 mg daily in the treatment of 40 previously untreated patients with advanced prostatic cancer. There was a good subjective response to both treatments. After 12 months, a response was demonstrated in 13 of 20 patients treated with flutamide and 8 of 20 patients treated with stilboestrol. The difference was not statistically significant. Treatment with stilboestrol caused more frequent, and more severe, side effects than flutamide.
With a median follow-up time of 160 weeks, the combination of bicalutamide plus LHRH-A was well tolerated and had equivalent time to progression and survival compared with flutamide plus LHRH-A. Treatment with bicalutamide plus LHRH-A resulted in longer median survival than treatment with flutamide plus LHRH-A.
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Niphtholid (25 mg/kg/dl for 60 days) significantly increases the LH and testosterone blood levels but has no marked effect on ++androstenedione and testosterone-estradiol-binding globulin levels in Chinchilla++ mature rabbits. The concentration of latter was elevated against a background of low testosterone and androstenedione and high LH levels in the castrated rabbits. The obtained results show that niphtholid exerts a continuous stimulating and pronounced effect on the rabbit pituitary-gonadal axis and simultaneously prevents the manifestation of suppressing androgen effect on testosterone-estradiol-binding globulin contents in the organism.
The charts of 1048 patients treated between 1991 and 1999 with transperineal realtime ultrasound-guided (103)Pd (Theraseed) implants were reviewed to assess the effects on serum prostate specific antigen (PSA) values and tissue (biopsy). Of the 1048 patients, 780 had sufficient data for this report. Preoperative total androgen blockade (leuprolide and flutamide) was used selectively in patients whose prostate size was >50 cc and those whose tumors had a Gleason score of >7.
This study was a single-blind clinical trial. The subjects were selected from a group of patient with PCOS and metabolic syndrome, who were referred to the midwifery clinic of Al-Zahra Hospital and Beheshti Hospital, Isfahan, Iran. A total of 111 subjects were randomly assigned to three groups: metformin, flutamide plus OCs, and simvastatin groups. The measurements were performed at baseline and after 6 months of therapy. Paired t-test, analysis of variance (ANOVA), and chi-square test were applied in this study.
To examine how androgens affect endocrine events associated with increased ovulation rate, gilts were injected with androgen receptor agonists, an antagonist, or a combination of both. Blood samples were collected hourly from Day 13 to estrus (Day 0 = onset of estrus) coincident with gilts (n = 6 per treatment) receiving daily treatments of vehicle (corn oil), 10 mg of testosterone, 10 mg of 5 alpha-dihydrotestosterone (dihydrotestosterone), 1.5 g of flutamide (an androgen receptor antagonist), testosterone plus flutamide, or dihydrotestosterone plus flutamide. Treatment of gilts with testosterone or dihydrotestosterone alone increased (P < 0.05) concentrations of FSH in serum, and these effects were blocked by cotreatment with flutamide. Estradiol-17beta and androstenedione concentrations in serum were increased (P < 0.05) at 2 h after injection of testosterone or testosterone plus flutamide but not after dihydrotestosterone treatment, probably because of the role of testosterone as a substrate for estradiol-17beta and androstenedione synthesis. There were no effects of the six treatments on serum concentrations of progesterone during luteolysis, but treating gilts with testosterone shortened (P < 0.05) the proestrous period. Total embryonic loss by Day 11 in gilts treated with dihydrotestosterone was reversed when gilts were cotreated with dihydrotestosterone plus flutamide. Results of this experiment indicated that androgen actions both increased FSH secretion and reduced embryonic survival by a mechanism(s) dependent on the androgen receptor.
Neoadjuvant hormonal therapy effectively reduces the volume of normal tissue exposed to high radiation doses in the majority of treated patients and decreases the potential morbidity of therapy.
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Treatment with flutamide has been associated with clinical hepatotoxicty. The toxicity, metabolism,and transport of flutamide were investigated using cultured human hepatocytes. Flutamide and its major metabolite, 2-hydroxyflutamide, caused an inhibition of taurocholate efflux in human hepatocytes with an IC50=75 microM and 110 microM, respectively. Treatment of hepatocytes with flutamide or 2-hydroxyflutamide for 24 h resulted in time- and concentration-dependent toxicity as assessed by inhibition of protein synthesis. Toxicity was greater after 1 h than after 24 h of treatment. Recovery in inhibition of protein synthesis by 24 h was attributed to the decreased presence of flutamide due to its metabolism. Flutamide was metabolized by hepatocytes to several metabolites, and formation of reactive intermediates of flutamide, as evidenced by the presence of glutathione-related adducts, was observed. Inhibition of flutamide metabolism by 1-aminobenzotriazole (ABT) resulted in enhancement of flutamide toxicity, which was associated with sustained levels of nonmetabolized drug. ABT also prevented the formation of reactive intermediates of flutamide. There was an additive toxicity when cells were treated with a combination of flutamide and 2-hydroxyflutamide. Simultaneous treatment with flutamide and acetaminophen (APAP) resulted in additive to synergistic toxic effects. Flutamide and APAP were found to have significant effects on each other's metabolism. Flutamide inhibited glucuronidation and sulfation of APAP, resulting in greater amounts of APAP available for bioactivation. APAP inhibited the hydroxylation of flutamide, and subsequent sulfation and acetylation of 4-nitro-3-(trifluoromethyl) aniline, a metabolite of flutamide. In summary, we suggest that inhibition of bile acid efflux by flutamide and its 2-hydroxy metabolite may play a role in flutamide-induced liver injury. Both flutamide and 2-hydroxyflutamide are responsible for cytotoxicity if not metabolized. The data also suggest a possible drug-drug interaction between flutamide and APAP, resulting in inhibition of flutamide metabolism and increased APAP bioactivation and toxicity.
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Outcomes of alternative (second-line) antiandrogen therapy in 112 patients with relapsing prostate cancer after first-line hormonal therapy were analyzed. A good response (prostate-specific antigen [PSA] decrease 50%) and a partial response (PSA decrease of 0–50%) by switching from bicalutamide (BCL) to flutamide (FLT) and from FLT to BCL were achieved in 35.4% (28/79) and 30.4% (24/79), and in 45.0% (9/20) and 20.0% (4/20) of cases, respectively. A good response and a partial response with the change from chlormadinone acetate (CMA) to a non-steroidal antiandrogen (FLT or BCL)and from a non-steroidal antiandrogen to CMA were obtained in 25.0% (2/8) and 37.5% (3/8), and in 20.0% (1/5) and 0% (0/5)of cases, respectively. In multivariate analyses, a second-line good response was significantly predictive of cause-specific survival from first therapy relapse to cancer death in all patients. Patients (52/112, 46.4%) with 30% decrease in PSA levels were associated with significantly better cause-specific survival as measured from the start of first-line treatment and first-line relapse.
Randomized, prospective clinical study.
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Gender-specific disparities have been observed in myocardium exposed to tumor necrosis factor-α (TNF). Male myocardium demonstrates greater loss in cardiac function in the presence of a given TNF level compared to female. In addition, we have previously demonstrated that estrogen has little influence on reducing TNF-caused myocardial dysfunction in female hearts, suggesting that male hormone - testosterone may be responsible for gender differences in TNF-mediated myocardial damage. Therefore, in this study, we hypothesize that endogenous testosterone plays a detrimental role in TNF-induced myocardial injury in male hearts.
Flutamide, sustained-release goserelin acetate, and a combination of these agents were effective in protecting the germinal epithelium of the rat during chemotherapy. A combination of flutamide and goserelin acetate provided the best protection. This study demonstrates for the first time the protective effect of flutamide and flutamide with goserelin acetate on the germinal epithelium during chemotherapy.
The Deleted in AZoospermia (DAZ) gene family plays an essential role in spermatogenesis and fertility in mammals. This gene family contains two autosomal genes, BOULE and DAZL (DAZ-Like), and the DAZ gene cluster in the Y chromosome. CDC25A (a cell cycle regulator) has been proposed as a putative substrate for the RNA-binding proteins of DAZ family. However, mechanisms regulating DAZ gene expression have been poorly investigated. We analyzed immunohistochemical localization of DAZL, BOULE and CDC25A, as well as the involvement of testosterone (T) and insulin-like growth factor 1 (IGF1) in the modulation of mRNA expression for DAZL, BOULE and CDC25A in the adult mouse testes. It was found that DAZL was mostly immunolocalized in spermatogonia, while BOULE and CDC25A were detected in spermatocytes and round spermatids. Three-color immunofluorescence showed that DAZL-positive cells also expressed proliferating cell nuclear antigen (PCNA). In vitro incubation of the testes showed that neither T nor IGF1 affected DAZL mRNA expression. However, either T or IGF1 increased BOULE mRNA expression. Antiandrogen flutamide abolished the T-induced increase in BOULE mRNA, but had no effect on the IGF1 induced increase in the mouse testes. Extracellular-signal-regulated kinase 1/2 (ERK1/2) inhibitor, U0126, prevented IGF1-induction of BOULE mRNA. It was found that IGF1 increased CDC25A mRNA expression and that U0126 - but not flutamide - abolished the IGF1-induced CDC25A mRNA expression. These results showed that IGF1 regulated the expression of BOULE and CDC25A mRNAs via ERK1/2 signaling and in T-independent pathway during spermatogenesis in the adult mouse testes.
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Flutamide administration to FZDR resulted in the reversal of abnormal systemic and renal alpha-1-mediated vasoconstriction and enhanced nitric oxide-mediated vasodilation. Flutamide caused a paradoxic but specific increase in renal perfusion during ET-1 and TXA2 receptor activation, which could be renoprotective in females. The salutary effects of flutamide on vascular reactivity in the FZDR may be mediated by a protein kinase C-dependent mechanism. These results are compatible with the notion that endogenous testosterone may regulate systemic and renal microcirculation in the female sex and in the type 2 diabetic state.
Flutamide has been used as an adjunct for decreasing the mortality from subsequent sepsis. Heatstroke resembles septic shock in many aspects. We hypothesized that heat-induced multiple organ dysfunction syndromes and lethality could be reduced by flutamide therapy. In heatstroke groups, mice were exposed to whole body heating (41.2°C, for 1h) in a controlled-environment chamber. The heat-stressed mice were returned to normal room temperature (24°C) after whole body heating. Mice still alive on day 4 of WBH treatment were considered survivors. Physiological and biochemical parameters were monitored for 2.5h post-WBH. Heatstroke mice were subcutaneously treated with flutamide (12.5-50mg/kg body weight in 0.05 ml) or vehicle solution (0.05 ml/kg body weight) once daily for 3 consecutive days post-WBH. We evaluated the effect of flutamide in heatstroke mice and showed that flutamide significantly (i) attenuated hypothermia, (ii) reduced the number of apoptotic cells in the hypothalamus, the spleen, the liver, and the kidney, (iii) attenuated the plasma index of toxic oxidizing radicals (e.g., nitric oxide metabolites and hydroxyl radicals), (iv) diminished the plasma index of the organ injury index (e.g., lactate dehydrogenase), (v) attenuated plasma systemic inflammation response molecules (e.g., tumor necrosis factor-α and interleukin-6), (vi) reduced the index of infiltration of polymorphonuclear neutrophils in the lung (e.g., myeloperoxidase activity), and (vii) allowed three times the fractional survival compared with vehicle. Thus, flutamide appears to be a novel agent for the treatment of mice with heatstroke or patients in the early stage of heatstroke.
Up to 32% of cultured cells exhibited spontaneous elevations of [Ca(2+)](i). The frequency of these elevations was reduced by nifedipine (10 microM), ryanodine (1 microM), and the adenylate cyclase inhibitor MDL 12,330A (20 microM). Compared to steroid-free cells, a 3-day incubation of cells with testosterone (only 3 nM) elevated basal, but not peak [Ca(2+)](i). In the presence of flutamide, all concentrations of testosterone tested elevated basal, but not peak [Ca(2+)](i). DHT (30 and 300, but not 3 nM) lowered peak and basal [Ca(2+)](i). Increased testosterone concentration dependently decreased resting cell cAMP (pIC(50): 7.64 +/- 0.29 nM).
Ninety-two and 68 patients underwent biopsies at 12 and 24 months, respectively, after the end of radiation therapy. While 62% of control patients at 12 months in Group 1 disclosed residual neoplasm, only 30% and 4% showed residual disease in groups 2 and 3, respectively (p = 0.00005). When looking at 24 months, 65, 28, and 5% showed residual cancer for groups 1, 2, and 3, respectively (p = 0.00001). The PSA measurements indicate also at 12 months a difference between the three groups (p < 0.0001), except at 24 months, the difference between the group 2 and 3 is no longer significant.
Six men being treated for advanced prostate carcinoma with flutamide/finasteride combination therapy developed painful gynecomastia, which was treated with tamoxifen 10 to 30 mg/day for 1 month. Clinical follow-up included breast measurements and determination of prostate-specific antigen (PSA), testosterone, and estradiol levels.