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There was no difference between the treatment arms in terms of time to biochemical or clinical progression and overall or disease-specific survival. There was no increase in cardiovascular mortality in the PEP arm. The PEP group had a higher prevalence of cardiovascular disease prior to the study and a significantly higher incidence of non-fatal ischemic heart events and heart decompensation during the study.
To facilitate the rational design of novel and more potent androgen receptor ligands, three-dimensional models for the human androgen receptor ligand binding domain bound to testosterone have been developed. These models of the androgen receptor were based on the crystal structure of the highly homologous human progesterone receptor ligand binding domain. The homology modeled androgen receptor was refined using unrestrained multiple molecular dynamics simulations in explicit solvent. Key H-bonding partners with the 17-hydroxy group and 3-keto group of testosterone are Asn705 and Thr877, and Gln711 and Arg752, respectively. These models show the presence of a unique unoccupied cavity within the androgen receptor binding pocket which may be valuable in the development of novel selective androgen receptor ligands. A qualitative analysis of amino acid mutations within the hAR binding pocket that affect ligand binding are consistent with these androgen receptor models. In addition to testosterone, the binding modes of several hydroxyflutamide-like nonsteroidal ligands for the androgen receptor are investigated using flexible docking with FlexX followed by refinement of the initial complexes with molecular dynamics simulations. These docking studies indicate that Asn705 is an important determinant in binding hydroxyflutamide and its derivatives by participating in H-bond interactions with the alpha-hydroxy moiety of these ligands. In addition, the nitro functionality mimics the 3-keto group of the natural ligand testosterone and is involved in H-bonding interactions with Gln711 and Arg752. From these docking studies, we suggest a mechanism for the enantioselective binding of chiral hydroxyflutamide derivatives and expand upon the previously reported structure-activity relationship for hydroxyflutamide and its derivatives.
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For patients with stage D2 prostate cancer and disease progression or an increasing PSA concentration, withdrawal of antiandrogen therapy with bicalutamide or flutamide may result in a PSA response. The time to PSA response is longer with bicalutamide than with flutamide. The clinical significance of the antiandrogen withdrawal phenomenon is unknown.
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The influence of testosterone (T) on progesterone (P) production by isolated rat ovarian granulosa cells was studied in vitro using a new replicate culture technique. Preantral granulosa cells from ovaries of estrogen-primed hypophysectomized immature female rats were cultured in the presence of graded concentrations of T, diethylstilbestrol (DES), cyproterone acetate (CPA), flutamide and the hydroxylated derivative of flutamide, Sch 16423. The accumulation of P in medium collected from granulosa cell cultures was measured by specific radioimmunoassay. Maximal P production by cultured granulosa cells was attained during the second day of culture and declined markedly thereafter. The presence of 10(-9), 10(-8) or 10(-7)M T elicited increases in P production 2.4, 8 and 11 times that of controls, respectively, during the initial 48 h of culture. Each concentration of T elicited enhanced P production within the first 24 h of culture. Granulosa cells cultured in control medium for 2 days did not respond to 10(-7)M T during the subsequent 3 days. DES at a high concentration in the medium (10(-5)M) markedly suppressed the response to 10(-9) and 10(-8)M T. At a lower concentration (10(-9)M) DES significantly enhanced the stimulatory effect of 10(-9)M T but did not alter the response to higher concentrations of T. Neither high nor low concentrations of DES influenced P production in response to 10(-7) M T. The stimulatory effects of T on P production were suppressed in the presence of a 100-fold molar excess of the anti-androgens, CPA or Sch 16423. The present data indicate that androgenic stimulation of P production by preantral granulosa cells is a specific receptor mediated event which is modulated by the presence of estrogen in vitro. It is suggested that androgen-responsive P production is a functional capacity which granulosa cells acquire at a very early stage of hormonal differentiation and may be of physiological consequence in the intraovarian control of follicular maturation in vivo.
We report a 58 years old male, presenting with malaise, weight loss and jaundice. An abdominal ultrasound showed multiple lymphadenopathies in the hepatic bilus and around the pancreas. Fine needle aspiration of these nodes demonstrated an undifferentiated carcinoma. Prostate specific antigen was over 100 ng/ml and a prostate biopsy demonstrated a high grade carcinoma. The patient was subjected to an orchiectomy and hormone therapy (flutamide). Jaundice subsided and he is well after 3 years of follow up and maintained hormone therapy.
Hormonal changes induced by the pure antiandrogen flutamide were studied in three postmenopausal metastatic breast cancer patients. The drug was administered at a dose of 250 mg, three times a day for 3-6 months. In each patient a sharp decrease of about 50% was observed in the circulating levels of DHT and DHEAS, irrespective of pretreatment values. A concomitant, although less pronounced, reduction in circulating testosterone, androstenedione and estradiol was found. A decrease in circulating steroids was associated with a 30% decrease in SHBG concentrations in two patients; in the third patient a 30% increase occurred. Androgens in urine, namely testosterone, androstanediol and 17-KS, decreased accordingly. In addition, a marked decrease in 17-OHCS occurred in two of the patients. These data indicate that flutamide is an effective antiandrogen in women and suggest two possible mechanisms by which the drug exerts its antiandrogenic activity: (a) inhibition of conversion of testosterone into the more active DHT, and (b) inhibition of synthesis of the adrenal precursors of active androgens. Minor variations in circulating LH and FSH were observed. Pretreatment prolactin values, which were higher than normal, dramatically decreased by 90% in one patient who had a partial remission of her disease, and they further increased in another patient who relapsed while on therapy.
DHT, but not testosterone (0.03-300 nM), elicited concentration-dependent elevations of [Ca(2+) ]i within 1 min of addition. These responses were blocked by the androgen receptor antagonist, flutamide (10 μM); the sarcoplasmic reticulum ATPase pump inhibitor, thapsigargin (1 μM); the inositol trisphosphate receptor inhibitor, 2-aminoethyldiphenyl borate (50 μM) and the PLC inhibitor, U-73122 (1 μM). Responses were also blocked by the L-type calcium channel blocker, nifedipine (1 μM), and by removal of extracellular calcium. A similar transient elevation of [Ca(2+) ]i was elicited by EGF (100 ng·mL(-1) ). The EGF receptor inhibitor, AG 1478 (30 nM), and the MMP inhibitor, marimastat (100 nM), blocked the DHT-induced elevation of [Ca(2+) ]i .
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We investigated the effects of GnRH analogs, different doses of testosterone (T), an androgen receptor antagonist (flutamide), and combinations of these on the recovery of spermatogenesis after irradiation. Treatment with a GnRH agonist (Lupron) for 10 weeks after irradiation reduced the intratesticular T concentration (ITT) to 4% of that in irradiated rats and serum FSH to undetectable levels without altering serum LH levels. Injection of a GnRH antagonist (Cetrorelix) at 3 weeks after irradiation suppressed LH, FSH, and ITT to <7%, 32%, and 10%, respectively, of levels in irradiated-only rats within 2 weeks; suppression was maintained for approximately 3 to 4 weeks. The percentage of tubules with differentiated germ cells (repopulation index, RI) was <0.6% at weeks 10 to 20 after irradiation. Spermatogenic recovery was induced by both the GnRH agonist (RI = 58% at week 10; 91% at week 20) and antagonist (RI = 70% at week 13). There was a dose-dependent suppression of testicular germ cell repopulation when T was combined with GnRH analogs. The ability of T to abolish the spermatogenic stimulatory effect of the GnRH antagonist was evident by the similar RI obtained for irradiated rats given antagonist + T or T alone. This suppression of GnRH-induced recovery of spermatogenesis by T could be reversed by flutamide. The RI best correlated with the degree of ITT suppression. In ITT-suppressed rats, the RI also showed an inverse correlation with serum T levels. Thus, T and/or its androgenic metabolites either directly or indirectly inhibit spermatogenic recovery after irradiation through an androgen receptor-mediated process. In addition, there was a close negative correlation between RI and FSH levels, and hence, a spermatogenic inhibitory role for FSH in the irradiated rats cannot be ruled out.
There was a substantial number of patients who found second-line AAT to be modestly effective. Flutamide was effective as an alternative antiandrogen for the patients' relapse treatment with bicalutamide in Japanese men.
Prostate carcinoma is one of the most frecuent cancers in men. Significant numbers of patients have regional lymph node and bone metastases during the course of the disease. Mediastinal lymphadenopathy and cutaneous metastases are uncommon and signify well-advanced disease. We report the case of a patient with prostate cancer who develops mediastinal lymphadenopathy, pulmonary nodules and cutaneous metastases 8 years after the diagnosis.
Our purpose was to determine the recurrence rate of hirsutism after 3 different antiandrogen therapies.
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The 16HBE-14o cells were stimulated with 5 ng/ml TGF-β1 for 3 days to induce EMT, with or without DHEA pretreatment, and assayed for epithelial or mesenchymal markers using Western Blot. The involvement of phosphoinositide 3-kinase (PI3K) -mediated signaling pathway was also evaluated, the epithelial cells were also incubated with pharmacological approaches (agonists and antagonists of Akt, LY294002 or IGF-1) or flutamide, the antagonist of androgen receptor. Results were analyzed using nonparametric statistical tests.
Estrogen is an active neuroprotectant and is presently investigated as a potential therapy against Alzheimer's disease for women. To determine if male hormones could also be neuroprotective, we investigated the effect of testosterone, methyltestosterone, and epitestosterone at physiological concentrations on primary cultures of human neurons induced to undergo apoptosis by serum deprivation. Serum deprivation significantly induces neuronal apoptosis in a protracted fashion. As expected, physiological concentrations of 17-beta-estradiol and transcriptionally inactive 17-alpha-estradiol protect neurons against apoptosis. Similar to 17-beta-estradiol, physiological concentrations of testosterone are also neuroprotective. Androgen receptors are present at 8 +/- 2 fmol/mg protein in the neuron cultures. The non-aromatizable androgen, mibolerone, is also neuroprotective and aromatase inhibitor, 4-androsten-4-OL-3,17-dione, does not prevent testosterone-mediated neuroprotection. In contrast, anti-androgen, flutamide, eliminates testosterone-mediated neuroprotection. Testosterone analog, methyltestosterone, showed androgen receptor-dependent neuroprotection that was delayed in time indicating that a metabolite may be the active agent. The endogenous anti-androgen, epitestosterone, also showed a slight neuroprotective effect but not through the androgen receptor. These results indicate that androgens induce neuroprotection directly through the androgen receptor. These data suggest that androgens may also be of therapeutic value against Alzheimer's disease in aging males.
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Phenacetin was withdrawn from the market because it caused renal failure in some patients. Many reports indicated that the nephrotoxicity of phenacetin is associated with the hydrolyzed metabolite, p-phenetidine. Acetaminophen (APAP), the major metabolite of phenacetin, is also hydrolyzed to p-aminophenol, which is a nephrotoxicant. However, APAP is safely prescribed if used in normal therapeutic doses. This background prompted us to investigate the difference between phenacetin and APAP hydrolase activities in human liver. In this study, we found that phenacetin is efficiently hydrolyzed in human liver microsomes (HLM) [CL(int) 1.08 +/- 0.02 microl/(min . mg)], whereas APAP is hardly hydrolyzed [0.02 +/- 0.00 microl/(min . mg)]. To identify the esterase involved in their hydrolysis, the activities were measured using recombinant human carboxylesterase (CES) 1A1, CES2, and arylacetamide deacetylase (AADAC). Among these, AADAC showed a K(m) value (1.82 +/- 0.02 mM) similar to that of HLM (3.30 +/- 0.16 mM) and the highest activity [V(max) 6.03 +/- 0.14 nmol/(min . mg)]. In contrast, APAP was poorly hydrolyzed by the three esterases. The large contribution of AADAC to phenacetin hydrolysis was demonstrated by the prediction with a relative activity factor. In addition, the phenacetin hydrolase activity by AADAC was activated by flutamide (5-fold) as well as that in HLM (4-fold), and the activity in HLM was potently inhibited by eserine, a strong inhibitor of AADAC. In conclusion, we found that AADAC is the principal enzyme responsible for the phenacetin hydrolysis, and the difference of hydrolase activity between phenacetin and APAP is largely due to the substrate specificity of AADAC.
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Based on this analysis, adjuvant long-term hormones compared to short-term hormones resulted in statistically significant improvements in bNED control, DMF, and CSF rates for patients with locally advanced nonmetastatic prostate cancer.
To investigate the hypothesis that maximal androgen blockade improves the outcome of patients with metastatic prostate cancer.
Twenty men (age range 56-87 years) with advanced prostate cancer were studied. All except one had metastatic disease confirmed by biopsy and/or radiological studies. One patient who had radiological findings suggesting a single hepatic metastasis was found to have focal fatty infiltration on biopsy obtained after FDHT-PET and was excluded from further data analysis. FDHT uptake was assessed semiquantitatively by determination of the standardized uptake value (SUV) and tumor-to-muscle ratio (T/M). Additionally, to assess the AR binding selectivity of FDHT, patients with one or more foci of abnormally increased FDHT accumulation were studied after administration of an AR antagonist (flutamide).
Leydig cell-conditioned media dose-dependently stimulated expression of transcription factor Foxp3 and secretion of IL-10 in splenic CD4+ T cells, an effect abolished by addition of the anti-androgen flutamide. In isolated Sertoli and peritubular cells, testosterone pre-treatment suppressed the LPS-induced inflammatory response on TNF-α mRNA expression, while no effect was evident in testicular macrophages (TM).
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Missense mutations in the androgen receptor (AR) contribute to the failure of hormonal therapy for prostate cancer (PCa), but the underlying molecular bases remain uncharacterized. Here, we describe a new AR variant found in a hormone-refractory metastatic PCa, in which threonine 575 in the DNA binding domain, and threonine 877 in the ligand-binding domain, were both replaced by an alanine. Using gene reporter assays, we demonstrate that the T575A mutation weakened transcriptional activity from promoters containing AR-specific responsive elements, while activity from promoters with AR-non-specific elements was enhanced. Data from gel shift experiments revealed a preferential binding of the T575A mutant to AR-non-specific motifs. We demonstrate that the two mutations T575A and T877A cooperate to confer new functional properties on the AR, and that the mutant AR functions simultaneously as a promiscuous AR due to the T877A mutation, and an unfaithful AR due to the T575A mutation.
Testosterone deficiency increases catalepsy and testosterone replacement can significantly be effective in catalepsy remission. It seems that the anticataleptic effect of testosterone is exerted through affecting on androgenic receptors.
The distribution of labeled antiandrogens, estrogens, and androgens has been studied in the rat and dog to elucidate the principles and limitations encountered when these agents are used in radioscanning the prostate. The bulk of the label is rapidly cleared in the biliary secretions and in the urine. The concentration of label in the prostate in comparison to other tissues such as the intestines limits the application of these agents in radioscanning of the prostate. The tissue distributions were confirmed by total body radioscans of rats and dogs receiving a labeled 3'-iodinated analog of the antiandrogen flutamide (Sch 13521 or 3'-trifluoromethyl-4'-nitroisobutyranilide).
The relative density of immune cell subtypes (CD3(+), CD8(+), CD20(+), CD56(+), CD68(+) and Foxp3(+)) was analyzed by immunohistochemistry in archived prostate specimens from control patients (radical prostatectomy only, n=40) and ADT-treated patients (ADT prior to radical prostatectomy, n=35) using an image analysis software and a whole-slide scanner.
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Between January 1992 and July 1994, 160 men with prostate cancer underwent radical retropubic prostatectomy (RP) and bilateral pelvic node dissection (PLND). Forty men (mean age 64.2 years) with either a higher clinical stage or a significant increase in serum prostate-specific antigen (PSA) level (P < 0.001) received induction ADT with a luteinizing hormone-releasing hormone (LH-RH) analogue alone (six patients), or with an anti-androgen (34 patients), 3-20 months before undergoing RP. The remaining 120 men (mean age 64 years) underwent surgery alone and served as historical controls. Prostatectomy specimens were evaluated using step-sections at 2-3 mm intervals and whole-mount reconstruction. The clinical and pathological results were compared.