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At least 685 records · Page 38Linked to original sources
PubMed1992

[Production of polyclonal antibody against human androgen receptor and immunohistochemical study of human androgen receptor in prostatic tissues].

We produced polyclonal antibody against human androgen receptor (hAR) by means of immunizing a rabbit with hAR fusion protein that was expressed in E. coli. In Western blot analysis, this antibody, NH27, recognized two protein bands at the site of 110 kDa and 107 kDa in androgen-independent human prostatic cancer cells (PC-3), transfected with full-length hAR expression plasmid DNA and at the site of 114 kDa and 108 kDa in androgen-dependent human prostatic cancer cells (LNCaP). In immunohistochemical examination with NH27, the nuclei of epithelial and stromal cells in human benign prostatic hyperplasia were mainly stained as did with AN1-15, commercially available hAR monoclonal antibody. Titer of NH27, however, was about five times more high than that of AN1-15. In prostatic cancer cells the nuclei were stained with NH27 as did with AN1-15. Intensity of staining was various between the nuclei of cancer cells. The polyclonal antibody, NH27, produced in the present study is useful in investigating the characterization of AR in androgen-dependent and -independent prostatic cancers.

Animals↗
PubMed2002

Synergistic activation of the androgen receptor by bombesin and low-dose androgen.

PURPOSE: Neuropeptide growth factors such as bombesinare implicated in progression to androgen-independent prostate cancer (PC). We examined the impact of bombesin on androgen receptor (AR)-mediated gene expression. EXPERIMENTAL DESIGN: The AR together with the AR-responsive probasin ARR(3)tk-luc or PSA-pPUE-ELB-luc promoter was cotransfected into Swiss 3T3 and PC-3 cells, both of which express high-affinity bombesin receptors; the cells were incubated with bombesin (0-50 nM) and dihydrotestosterone (DHT; 0-10 nM), and luciferase activities were measured. DHT increased transcription approximately 40-fold at doses of 1 and 10 nM but had no effect at 10 pM. Bombesin alone, or with 1 or 10 nM DHT, did not further increase transcription. However, 5 nM bombesin and 10 pM DHT, doses that by themselves had no effect, resulted in a approximately 20 fold increase in transcription (P < 0.005). This synergistic effect was blocked by bombesin receptor antagonists and recombinant neutral endopeptidase, which hydrolyzes bombesin. Bombesin and DHT together also increased binding of nuclear extracts from PC-3 cells transfected with AR to a consensus androgen response element in mobility shift assays and increased the level of secreted prostate-specific antigen in LNCaP cell supernatant compared with DHT or bombesin alone. Immunoprecipitation of AR from (32)P-labeled LNCaP cells revealed that 5 nM bombesin + 10 pM DHT induced AR phosphorylation comparable with 1 nM DHT, whereas bombesin or 10 pM DHT alone did not. CONCLUSIONS: These data indicate that bombesin can synergize with low (castrate) levels of DHT to induce AR-mediated transcription and suggest that neuropeptides promote AR-mediated signaling in androgen-independent prostate cancer.

Bombesin↗
PubMed2002

In vivo modulation of androgen receptor by androgens.

AIM: To study the effect of androgen and antiandrogen on the level of androgen receptor (AR) mRNA. METHODS: The total RNA was extracted from the prostate and analyzed by slot blot analysis. The blots were hybridized with AR cDNA probe and 1A probe (internal control) and autoradiography was performed. The intensity of signal was measured with a densitometer and the ratio of AR RNA and 1A RNA was calculated. RESULTS: Androgenic deprivation produced by castration decreased the weight of the prostate and increased the levels of AR mRNA. Treatment of the castrated rats with testostrone increased the weight of prostate and decreased the levels of AR mRNA. Treatment of normal rats with flutamide decreased the weight of the gland and increased the levels of AR mRNA. CONCLUSION: Androgens produce proliferative effect on the prostate and negatively regulate the AR transcription.

Animals↗
PubMed2002

Studies with CWR22 xenografts in nude mice suggest that ZD1839 may have a role in the treatment of both androgen-dependent and androgen-independent human prostate cancer.

PURPOSE: These studies examined the effect of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 ("Iressa")(3) on CWR22 prostate tumors in nude mice. The effect of ZD1839 was also examined in combination with either bicalutamide ("Casodex") or cytotoxic agents against a hormone-dependent or -independent variant of CWR22, respectively. EXPERIMENTAL DESIGN: The xenografts were grown for 4-7 days, then tumor measurements were made and therapy initiated. ZD1839 and bicalutamide were given p.o. on a once-daily, 5-day schedule for 2 successive weeks. Carboplatin and paclitaxel were given every 3-4 days for a total of four doses. Measurements of tumor volume were made twice weekly during treatment and for 2 weeks after treatment. The effect of ZD1839 on EGFR function was assessed by Western blotting of EGFR and its phosphorylated form in CWR22 and variant tumors before and after treatment with this agent. RESULTS: ZD1839 at its maximum tolerated dose (150 mg/kg) inhibited the growth of androgen-dependent CWR22 by 54%, and the growth of two variants with different degrees of androgen independence and androgen receptor gene expression (CWR22LD1 and CWR22RV1) by 76%. The effects of ZD1839 were similar to those recorded for phosphorylation of EGFR as determined by Western blotting. Coadministration of ZD1839 at its maximum tolerated dose markedly increased the antiproliferative action of the antiandrogen bicalutamide against CWR22LD1. In fact, combining ZD1839 with a suboptimal dose of bicalutamide was more effective than a higher dose of bicalutamide alone. Coadministration of ZD1839, which required a 2-3-fold attenuation of dose to avoid toxicity, also markedly increased the therapeutic activity of carboplatin and paclitaxel against CWR22RV1, bringing about regression to a degree not seen with either agent alone. Tumor-free mice were seen only with the combination of ZD1839 and paclitaxel. CONCLUSIONS: The results obtained in these related and highly relevant models of human prostate cancer suggest that ZD1839 may have a role in enhancing existing treatments of androgen-dependent and -independent forms of this disease in patients.

Anilides↗
PubMed2003

Androgens and FSH affect androgen receptor and aromatase distribution in the porcine ovary.

In the present study the authors investigated whether androgens could interact with FSH to induce aromatase and androgen receptor expression in porcine granulosa cells. Dissected whole porcine follicles (small, medium, and large) were incubated for 8 hours in M199 medium supplemented with testosterone (10(-7) M), FSH (100 ng/ml) or both those hormones. After incubation, the follicles were fixed and immunostained to visualise androgen receptor and aromatase. In cultures of granulosa cells isolated from small and large follicles, oestrogen secretion was measured by appropriate RIA. Incubation of follicles with testosterone and FSH increased aromatase immunoreactivity in preantral and early antral (i.e. small) follicles. The immunostaining for androgen receptor was slightly higher in medium follicles, while such hormonal stimulation had no effect on small and large follicles. Moreover, granulosa cells isolated from small follicles cultured with both testosterone and FSH produced more estradiol than control cultures (40 pg vs. 100 pg/10(5) cells). The level was relatively close to that obtained in the culture of control granulosa cells isolated from large preovulatory follicles (105 pg/10(5) cells). These results indicate that testosterone acts synergistically with FSH to increase aromatase expression in the small porcine follicles.

Animals↗
PubMed1991

Association of the Hind III polymorphism with the androgen receptor gene in partial androgen insensitivity syndrome.

Partial androgen insensitivity syndrome (PAIS) is an X-linked disorder resulting from defects in the intracellular androgen receptor (AR). The cloning of the AR cDNA has provided the molecular tools to identify gene abnormalities. Gene deletions being the exception in PAIS, prenatal diagnosis of PAIS resulting from a single base mutation in high risk families is not practical unless the mutation is already known. Brown et al. (1989) reported that 10% of normal X chromosomes present a Hind III 6.7/3.5 kb polymorphism. In this study, we report the association of the Hind II polymorphism in a woman whose son has a PAIS associated with a very low androgen receptor concentration: we differentiated the two maternal X chromosomes and characterized the affected allele. These data demonstrate that the presence of Hind III polymorphic fragments could be used in prenatal diagnosis of androgen insensitivity syndrome in high risk families.

Alleles↗
PubMed1991

[Regularities in androgen reception in rat liver and its role in realizing direct androgenous effects].

The content of androgen receptors (AR) in the cytosol and nuclear fractions of rat liver cells was studied by using the radioligand method. It was found that the nuclear AR content depends on the sex of animals as well as on the initial level of AR in the cytosol fraction. Elevation of AR concentration (p less than 0.05) in liver nuclei of different groups of animals was noted one hour after injection of 100 micrograms of methyltrienolone (R-1881). This elevation correlated positively with the initial level of AR in the cytosol. The accumulation of AR in liver nuclei was more pronounced in intact males than in females. A direct positive correlation between the initial level of cytosol AR and the final regulatory effect of androgens on the hepatic AR content (r = 0.955, n = 6, p less than 0.02) and on the content of the hepatic unusual estrogen-binding protein (UEBP) (r = 0.957, n = 9, p less than 0.001) were found. It is concluded that androgens induce in liver nuclei the accumulation of AR whose level correlates with that of the initial cytosolic AR. The latter reflects the efficiency of the direct effect of androgens on liver cells.

Animals↗
PubMed1990

Effect of estramustine phosphate on free androgens. A comparative study of the effect of orchiectomy and estramustine phosphate on free androgens in patients with prostatic cancer.

Total serum testosterone, serum testosterone binding globulin and free androgen index were determined before and during treatment in 14 patients with previously untreated disseminated prostatic cancer. Six patients received estramustine phosphate and six other patients underwent orchiectomy. Two further patients received estramustine phosphate because of tumor progression one and two years after orchiectomy. The result of the study indicates that estramustine phosphate is significantly more effective than orchiectomy in eliciting low levels of free androgens. This complete androgen ablation is produced by a depression of total testosterone and a concomitant increase of total serum testosterone binding globulin which yields a free androgen index an average 4.6 times lower in estramustine phosphate treated patients than in patients who underwent orchiectomy.

Androgens↗
PubMed1981

Androgen receptor protein in the androgen-dependent Dunning R-3327 prostate carcinoma.

The rat prostate carcinoma (Dunning R-3327) contains a relatively high concentration of androgen receptor (80 to 150 fmol/mg cytosol protein). We characterized this receptor for comparison with androgen receptors in normal organs of the rat. Binding of testosterone and dihydrotestosterone was of high affinity (Ka = 2 X 10(9) M). Rates of dissociation were slow (t 1/2 testosterone = 60 hr; t 1/2 dihydrotestosterone = approximately 160 hr). At low ionic strength, the receptor was in an 8S form which dissociated to 4.5 to 5.0S in the presence of 0.4 M KCl. Fractionation of [3H]dihydrotestosterone cytosol by chromatography on phosphocellulose yielded a single peak of radioactivity eluting at 0.2 M Cl-. Determination of size at high ionic strength by gel filtration chromatography and sucrose gradient centrifugation indicated a Stokes radius of 53 A and sedimentation coefficient of 5S (M.W. 115,000). Cytosols occasionally yielded a second peak of radioactivity eluting from phosphocellulose at 0.29 M Cl-. This fraction contained a smaller receptor [36 A, 3.6S (M.W. 55,000)]. Both receptor forms were observed in cytosols from the normal dorsal prostate. The larger high-salt form of the receptor is identical to native androgen receptor in normal tissues. Smaller receptor forms in the tumor and in normal androgen-responsive tissues have been shown previously to result from proteolytic cleavage of the native receptor during extraction.

Animals↗
PubMed1997

Potentiation of the antiangiogenic ability of linomide by androgen ablation involves down-regulation of vascular endothelial growth factor in human androgen-responsive prostatic cancers.

Linomide is a p.o. active antiangiogenic agent that has been demonstrated to be effective in suppressing the in vivo growth of rat and human prostatic cancer xenografts. The present studies were conducted to determine whether the angiogenic molecules, vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) and basic fibroblast growth factor (bFGF) are expressed in vitro by DU-145, PC-3, TSU-PR1, and LnCaP human prostate cancer cell lines and whether Linomide inhibits the secretion of these angiogenic molecules. Additionally, two different androgen-responsive human prostatic cancer xenograft models (i.e., PC-82 and A-2) were used to determine whether androgen ablation-induced reduction in tumor growth is associated with a reduction in tumor VEGF and/or bFGF levels. These studies demonstrated that both VEGF and bFGF proteins are expressed to different degrees in the human prostatic cancer cell lines. The secretion of VEGF but not bFGF is up-regulated by hypoxia. Linomide is unable to inhibit either basal or hypoxia-induced secretion of VEGF. Linomide also has no effect on secreted bFGF levels. Castration inhibited tumor VEGF but had no effect on bFGF levels in both the androgen-responsive PC-82 and A-2 human prostatic cancers when grown in severe combined immunodeficient mice. When given in combination, castration potentiated the inhibition of tumor growth induced by Linomide alone. This potentiation is not due to a further inhibition in tumor VEGF levels induced by castration. Although both castration and Linomide inhibit angiogenesis, the former accomplishes it by inhibiting VEGF secretion, whereas the latter has multiple effects at several steps in the angiogenic process other than VEGF secretion. Based on their different but complementary mechanisms of action, simultaneous combination of androgen ablation with Linomide enhances the anti-prostatic cancer efficacy compared to either monotherapies alone and warrants testing in humans.

Adenocarcinoma↗
PubMed1979

Anti-androgen TSAA-291. I. Anti-androgenic effects of a new steroid TSAA-291 (16 beta-ethyl-17 beta-hydroxy-4-oestren-3-one) and its derivatives.

Anti-androgenic properties of newly synthesized steroidal compounds, TSAA-291 and its derivatives, were studied in the rat. (1) Subcutaneous administrations of TSAA-291 and TSAA-272 were effective in depressing the weight of seminal vesicles and ventral and dorsal prostates in the adult rat. (2) TSAA-291, TSAA-328 and TSAA-272 were shown to be anti-androgenic by the subcutaneous or oral route in the immature castrated male rat treated with testosterone propionate. The dose-response curves of all the test agents expressed in terms of percentage inhibition were approximately parallel to each other. Cyproterone acetate depressed the weight of levator ani muscle dose-dependently, whereas TSAA-291, TSAA-328 and TSAA-330 did not inhibit the muscle weight in a dose range sufficiently effective in inhibiting the weight of seminal vesicles and ventral and dorsal prostates. (3) TSAA-291 was also anti-androgenic against androstenedione and dehydroepiandrosterone. (4) Local administration of the anti-androgenic compounds into the left seminal vesicle or left testis of the young adult rat depressed the weight of the seminal vesicle or testis on the treated side as compared with the vehicle-injected contra-lateral side.

Androgen Antagonists↗
PubMed1998

Methylation of the androgen receptor promoter CpG island is associated with loss of androgen receptor expression in prostate cancer cells.

Androgen-independent metastatic prostate cancer is characterized by a heterogeneous loss of androgen receptor (AR) expression among tumor cells. In this study, we evaluate DNA hypermethylation as a potential transcriptional regulatory mechanism in AR-negative prostate cancer cell lines. Nucleotide sequence analysis demonstrates an approximately 15-kb CpG island in the AR gene that encompasses the transcription start site and exon 1. Using Southern blotting with methylation-sensitive restriction enzymes and methylation-specific PCR, we find aberrant methylation in the AR expression-negative cell lines Du145, DuPro, TSU-PR1, and PPC1. Incomplete methylation in the AR CpG island is also seen in normal female breast and ovarian tissues consistent with the inactivation of one X chromosome by hypermethylation. In contrast, prostate cancer cell lines LNCaP and PC3 express AR and are unmethylated. Normal prostate epithelial cell strains demonstrate no methylation. Exposure of AR-negative prostate cancer cell lines to 5-aza-2' deoxycytidine, a demethylating agent, induces the reexpression of AR RNA in DuPro and TSU-PR1. This reexpression is associated with a demethylation of this region. Prostate-specific antigen, an androgen-responsive gene, is also specifically induced in these lines after AR reexpression. Therefore, in vitro DNA methylation of the 5' CpG AR island may be associated with the loss of AR expression. Furthermore, our results demonstrate that treatment with demethylating agents may engender the reexpression and function of the androgen receptor in AR-negative cell lines.

CpG Islands↗
PubMed1997

Vinclozolin and p,p'-DDE alter androgen-dependent gene expression: in vivo confirmation of an androgen receptor-mediated mechanism.

Vinclozolin and p,p'-DDE induce antiandrogenic developmental effects in vivo and are potent inhibitors of androgen receptor (AR) binding and AR-dependent gene expression in vitro. To determine whether this molecular mechanism is operative in vivo, the effects of these compounds on two androgen-regulated prostatic mRNAs were studied. Rats were sham operated or castrated and immediately implanted with one or two empty 2.5-cm silastic capsules or with one (1x) or two (2x) 2.5-cm capsules containing testosterone (T). T-implanted rats were treated by gavage for 4 days with vehicle (corn oil), vinclozolin (200 mg/kg/day), p,p'-DDE (200 mg/kg/day), or the antiandrogen flutamide (100 mg/kg/day) as a positive control. Vinclozolin, p,p'-DDE, and flutamide all induced a reciprocal decline in seminal vesicle (p < 0.01) and prostate (p < 0.01) weight as well as a reduction in immunohistochemical staining of AR in epididymal nuclei compared to vehicle-treated T-implanted controls. Specific AR antagonism was assessed by determining the ability of these chemicals to induce a testosterone-repressed prostatic message (i.e., TRPM-2) and/or repress a testosterone-induced prostatic message (i.e., prostatein subunit C3). Densitometry scans of Northern blots indicated that vinclozolin, p,p'-DDE, and flutamide each induced TRPM-2 mRNA and repressed C3 mRNA compared to vehicle-treated T-implanted controls. These antiandrogenic effects were competitively reduced in castrate rats implanted with two 2.5-cm T capsules (2x), where serum T levels were elevated more than twofold above physiological levels. Taken together, these data indicate that vinclozolin and p,p'-DDE act as antiandrogens in vivo by altering the expression of androgen-dependent genes.

Androgen Antagonists↗
PubMed1987

Linkage analysis with RFLPs in families with androgen resistance syndromes: evidence for close linkage between the androgen receptor locus and the DXS1 segment.

Three families with androgen resistance syndromes--two with testicular feminization and one with Reifenstein syndrome--have been studied for linkage analysis. Using three cloned DNA sequences from the centromere region and the proximal long arm of the X chromosome (p8, pDP34, and S9, which define respectively the chromosomal segments DXS1, DXYS1, and DXS17), we found no recombination between the DXS1 locus and the mutant genes in the three families. Assuming that these disorders are the result of allelic mutations at the same locus for the androgen receptor, we can conclude that there is a close linkage between DXS1 and the androgen receptor locus, with a maximum lod score zeta = 3.5 at a recombination fraction theta = 0.0 using the LIPED program (Ott 1974).

Androgen-Insensitivity Syndrome↗
PubMed1994

The effect of androgens and antiandrogens on the immunohistochemical localization of the androgen receptor in accessory reproductive organs of male rats.

The androgen receptor (AR) was localized immunohistochemically after different hormonal treatments in the ventral prostate, coagulating gland, seminal vesicle and epididymis of the adult rat. In the untreated controls AR-immunoreactivity was confined to the cell nuclei. One week after castration or treatment with the gonadotropin-releasing hormone antagonist Cetrorelix (150 micrograms/animal per day) a cytoplasmic staining occurred in the epithelial cells of the ventral prostate and in part of the coagulating gland and seminal vesicle. In contrast, the AR remained exclusively in the nuclei in the epididymal epithelium and the glandular smooth muscle layer even after 2 weeks of androgen depletion. Bolus injections of either dihydrotestosterone (1 mg/kg), the antiandrogen flutamide (40 mg/kg), or the novel non-steroidal antiandrogen casodex (40 mg/kg) to androgen-depleted animals eliminated cytoplasmic AR-immunoreactivity and restored the nuclear staining pattern in the ventral prostate. A sustained 2-week treatment with the antiandrogens resulted in a loss of weight in all organs but did not alter the distribution of AR-immunoreactivity. The data show an apparent cytoplasmic/nuclear ligand-dependent translocation of the AR in the ventral prostate, coagulating gland and seminal vesicle but not in the epididymis of the adult rat.

Amino Acid Sequence↗
PubMedDate not supplied

[Clinical aspects of the disordered androgen effect (the androgen resistance syndrome)].

The genetic, biochemical, clinical and endocrinological features of four distinct syndromes are described in which defective virilization in genetic and gondal men appears to result from resistance to androgen action. The clinical appearance of these forms of intersexuality covers the whole spectrum of phenotypical female patients to phenotypically normal appearing men with infertility. Based on studies with cultured genital skin fibroblasts three defects on the level of the androgen target organ can be differentiated in these syndromes: 1. Defective testosterone metabolism, 2. Anomalies of the androgen receptor and a 3. Postreceptor defect.

Adolescent↗
PubMed1999

From HER2/Neu signal cascade to androgen receptor and its coactivators: a novel pathway by induction of androgen target genes through MAP kinase in prostate cancer cells.

Overexpression of the HER2/Neu protooncogene has been linked to the progression of breast cancer. Here we demonstrate that the growth of prostate cancer LNCaP cells can also be increased by the stable transfection of HER2/Neu. Using AG879, a HER2/Neu inhibitor, and PD98059, a MAP kinase inhibitor, as well as MAP kinase phosphatase-1 (MPK-1), in the transfection assay, we found that HER2/Neu could induce prostate-specific antigen (PSA), a marker for the progression of prostate cancer, through the MAP kinase pathway at a low androgen level. Reporter assays and mammalian two-hybrid assays further suggest this HER2/Neu-induced androgen receptor (AR) transactivation may function through the promotion of interaction between AR and AR coactivators, such as ARA70. Furthermore, we found this HER2/Neu --> MAP kinase --> AR-ARAs --> PSA pathway could not be blocked completely by hydroxyflutamide, an antiandrogen used in the treatment of prostate cancer. Together, these data provide a novel pathway from HER2/Neu to AR transactivation, and they may represent one of the reasons for the PSA re-elevation and hormone resistance during androgen ablation therapy in prostate cancer patients.

Androgen Antagonists↗
PubMed2002

A glucocorticoid-responsive mutant androgen receptor exhibits unique ligand specificity: therapeutic implications for androgen-independent prostate cancer.

The cortisol/cortisone-responsive AR (AR(ccr)) has two mutations (L701H and T877A) that were found in the MDA PCa human prostate cancer cell lines established from a castrated patient whose metastatic tumor exhibited androgen-independent growth. Cortisol and cortisone bind to the AR(ccr) with high affinity. In the present study, we characterized the structural determinants for ligand binding to the AR(ccr). Our data revealed that many of the C17, C19, and C21 circulating steroids, at concentrations that are found in vivo, functioned as effective activators of the AR(ccr) but had little or no activity via the wild-type AR or GRalpha. Among the synthetic glucocorticoids tested, dexamethasone activated both GRalpha and AR(ccr), whereas triamcinolone was selective for GRalpha. In MDA PCa 2b cells, growth and prostate-specific antigen production were stimulated by potent AR(ccr) agonists such as cortisol or 9alpha-fluorocortisol but not by triamcinolone (which did not bind to or activate the AR(ccr)). Of the potential antagonists tested, bicalutamide (casodex) and GR antagonist RU38486 showed inhibitory activity. We postulate that corticosteroids provide a growth advantage to prostate cancer cells harboring the promiscuous AR(ccr) in androgen-ablated patients and contribute to their transition to androgen-independence. We predict that triamcinolone, a commonly prescribed glucocorticoid, would be a successful therapeutic agent for men with this form of cancer, perhaps in conjunction with the antagonist casodex. We hypothesize that triamcinolone administration would inhibit the hypothalamic-pituitary-adrenal axis, thus suppressing endogenous corticosteroids, which stimulate tumor growth. Triamcinolone, by itself, would not activate the AR(ccr) or promote tumor growth but would provide glucocorticoid activity essential for survival.

Androgen Antagonists↗