Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antiandrogens are compounds able to block the effect of androgens directly on their target cells by inhibiting their binding to the androgen receptor (AR). Two chemical classes of antiandrogens are presently on the market or in clinical trials: steroids (cyproterone, megestrol acetates), and nonsteroids (flutamide, nilutamide). Steroid antiandrogens interact not only with AR but also with progestin and glucocorticoid receptors and thus give rise to progestin and glucocorticoid effects. By contrast, nonsteroid antiandrogens interact only with AR and are thus devoid of other hormonal or antihormonal activities. Nilutamide does not need to be transformed into an active metabolite, unlike flutamide, and interacts with dog, rat, and human prostate AR in vitro. Its kinetics lead to a prolonged interaction with AR in vivo after administration to rats. In prostate cancer treatment, it is necessary to combine an antiandrogen to surgical or chemical (estrogens, LH-RH agonists) castration to obtain a complete suppression of androgens. The antiandrogen will block specifically, at the target site, the trophic effect of adrenal androgens left intact by castration, and the secretion of which can only be suppressed by treatments (adrenalectomy, aminoglutethimide, ketoconazole) that also suppress corticoid synthesis. We have shown that nilutamide counteracts the trophic effect, on the prostate of castrated rats, of adrenal androgens administered continuously (minipumps) at circulating levels similar to those recorded in castrated men. Nilutamide will also impede the flare-up effect of the testosterone increase induced by LH-RH agonists at the beginning of treatment. We have shown in the rat treated with buserelin that the increase in prostate weight observed during the initial days of treatment by the LH-RH agonist can be inhibited by a combined treatment with nilutamide. This combined treatment "nilutamide plus castration" has been tested in an experimental androgen-dependent cancer model, the Shionogi tumor. The administration of nilutamide to mice, castrated twenty-four hours before the inoculation of tumor cells, delayed the appearance of tumors and reduced their number. Finally, the absence of androgen effect and the antiandrogen activity of the product were also demonstrated in human tumor cells in culture (T-47 D cells) transfected with the MMTV androgen-dependent promoter coupled with the CAT reporter gene.
 ...
PMID:Pharmacology of antiandrogens and value of combining androgen suppression with antiandrogen therapy. 199 2

Previously, histologic precision in the diagnosis of urologic cancers had, for some time, remained stable. More recently, variations in classifications of testis tumors, prostate cancer, and to some degree, bladder tumors, have been introduced. Most systems have in concurrence a desire or an attempt to infer better prognostic assessment in the overall results to treatment. With the advent of additional biological markers or direct enzymatic measurements, e.g., in prostate cancer, further improvements in identifying at risk populations, responses to treatment, and possible indications for variations in treatment, have ensued. These developments alone unquestionably mark the greatest area of change in the recent decade. The extent of disease assessment prior to definitive therapy, whether by arteriography, ultrasound, CAT scanning, or an occasional lymphangiography, has also influenced or modified treatment decisions. For continuing care and follow-up, several of these noninvasive techniques are now becoming included in the more standard approaches. Noninvasive techniques have been introduced for the therapy of renal tumors such as inducing infarction of the primary tumor. Endoscopic ultrasonic techniques have been particularly useful in assessing the size of pelvic tumors and response to treatment, even in detection of unexpected multiple primaries or metastatic extensions. Overall, the precision in urologic cancer, both for diagnostic and detection purposes, has been increased with these introductions.
 ...
PMID:The diagnosis and detection of urogenital cancers. 616 54

Incubation of whole LNCaP cells in suspension with tritium labeled cortisol revealed two major and one minor radioactive product. Of the major products, one migrated with an Rf value identical to cortisol (Kendall's compound "F"), and the second migrated with an Rf value similar to nonradioactive cortisone (Kendall's compound "E"); the third minor product comigrated with 21-acetylated cortisol. The conversion of cortisol to cortisone was linear with respect to cell number, and conversion reached a plateau after 120 min of incubation at 37 degrees C. One half of the cortisol was converted to cortisone within 2 h of incubation at 37 degrees C. This conversion was nicotine amide dinucleotide (NAD) dependent. Low levels of transcription activation by cortisol were documented in LNCaP cells transfected with glucocorticoid and androgen responsive mouse mammary tumor virus-bacterial chloramphenicol acetyltransferase chimeric gene (MMTV-CAT). Hormone binding assay and transactivation analysis revealed the presence of a functional mineralocorticoid receptor in LNCaP cells. Treatment of transfectants with F in the presence of carbenoxolone, a potent inhibitor of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD), resulted in a two orders of magnitude increase in measurable CAT activity. The addition of the reduced form of nicotine amide dinucleotide (NADH) in the presence of 10(-7) M E stimulated measurable CAT activity in LNCaP cells. In conferring aldosterone specificity in mineralocorticoid target tissues, 11 beta-HSD may have an important role as "gate keeper" in allowing a specific androgen response in hormone responsive LNCaP prostate cancer cells.
 ...
PMID:11 beta-Hydroxysteroid dehydrogenase and tissue specificity of androgen action in human prostate cancer cell LNCaP. 803 14

Human androgen receptor (hAR) is a ligand-dependent transcription factor that mediates androgen-induced actions on target tissues. Transfection studies in the human prostate cancer cell line LNCaP examine the ability of dihydrotestosterone (DHT), hydroxyflutamide (HO-FLU), cyproterone acetate (Cypro.A), and RU 23908-10 to stimulate or to inhibit the transcription activation of mouse mammary tumor virus-bacterial chloramphenicol acetyltransferase (MMTV-CAT). DHT stimulated transcription activation of MMTV-CAT gene in LNCaP cells in a dose-dependent manner. HO-FLU, Cypro.A, and RU 23908-10, though only partially, also stimulated the transcription activation of MMTV-CAT. Despite this, 100- to 1,000-fold molar excess of all antiandrogens inhibited the agonistic activity of 10 nM DHT in this system. Receptor binding assays confirmed that HO-FLU, Cypro.A, and RU 23908-10 competed with DHT for AR binding in LNCaP cells. Western blot analysis using AR antipeptide antibodies raised in rabbits revealed the presence of two AR protein bands in LNCaP cells, following treatment with antiandrogens. Increasing doses of HO-FLU stimulated the expression of the 114-kDa AR by 2.5-fold, but did not affect the 108-kDa AR. Increasing doses of Cypro.A and RU 23908-10 decreased the levels of both the 114-kDa and the 108-kDa AR. Although the exact nature of 108-kDa and 114-kDa AR in LNCaP cells is still unknown, these data suggest that the regulatory actions of each individual antiandrogen on AR expression in LNCaP cells may be different.
 ...
PMID:Antiandrogens inhibit human androgen receptor-dependent gene transcription activation in the human prostate cancer cells LNCaP. 814 66

The p53 gene is known to be one of the frequently altered tumor suppressor genes, involved in the oncogenesis of a wide spectrum of human malignant tumors. We investigated mutational events of the p53 gene in 18 clinically untreated prostate cancers. Direct sequencing analysis demonstrated that 1 of 18 cases harbored point mutation in the highly conserved transcript region. The case showed CAT at codon 273 instead of wild-type CGT, substituting the encoded amino acid form histidine to arginine. The case had previously revealed homozygous loci on 17p, including the p53 locus, by restriction fragment length polymorphism analysis. The other 17 cases harbored neither mutation nor small deletion. It is concluded that point mutation of the p53 gene is a infrequent event in the oncogenesis of untreated prostate cancer.
 ...
PMID:Point mutation of the p53 gene is an infrequent event in untreated prostate cancer. 876 16

The expression of the androgen receptor (AR) gene is regulated by androgens. Although androgens down-regulate AR mRNA in most cell lines and tissues, including the prostate, up-regulation occurs in some tissues. Androgen-mediated reduction in AR mRNA is reproduced in COS1 cells and in the androgen-sensitive human prostate cancer cell line LNCaP when each expresses the AR cDNA. We have previously established that the AR cDNA contains the requisite sequences for this down-regulation. Here we shown that androgen promoted up-regulation of AR mRNA in two androgen-independent human prostate cancer cell lines, PC3 and DU145, when each was transfected with a human AR cDNA. This effect was due to the AR cDNA and not to the heterologous promoter driving AR expression. In addition to up-regulation of AR mRNA, androgen induced comparable increases in AR protein levels in PC3 cells stably expressing an AR cDNA (PC3/AR). Up-regulation of AR in PC3/AR cells was accompanied by failure of these cells to undergo desensitization or inactivation of AR following prolonged (96 h) androgen administration, whereas the same conditions resulted in desensitization of AR transactivation in LNCaP cells and in CVl cells that stably express the AR cDNA. Androgen treatment of PC3/AR cells resulted in induction of an androgen-regulated reporter gene (MMTV-CAT) as well as the native prostate-specific antigen gene, which is silent in untransfected PC3 but is androgen up-regulated in LNCaP and in the prostate. These results suggest that ectopic expression of AR in androgen-independent prostate cancer cell lines establishes both typical and atypical androgenic responses in a target gene-specific manner. Androgenic up-regulation of AR cDNA expression may be due to distinct signaling mechanisms that influence androgen action in androgen-independent prostate cancer cells.
 ...
PMID:Androgenic up-regulation of androgen receptor cDNA expression in androgen-independent prostate cancer cells. 888 19

An androgen receptor (AR) gene mutation identified in the androgen-dependent human prostate cancer xenograft, CWR22, changed codon 874 in the ligand-binding domain (exon H) from CAT for histidine to TAT for tyrosine and abolished a restriction site for the endonuclease SfaNI. SfaNI digestion of AR exon H DNA from normal but not from prostate cancer tissue indicated H874Y is a somatic mutation that occurred before the initial tumor transplant. CWR22, an epithelial cell tumor, expresses a 9.6-kb AR mRNA similar in size to the AR mRNA in human benign prostatic hyperplasia. AR protein is present in cell nuclei by immunostaining as in other androgen-responsive tissues. Transcriptional activity of recombinant H874Y transiently expressed in CV1 cells in the presence of testosterone or dihydrotestosterone was similar to that of wild type AR. With dihydrotestosterone at a near physiological concentration (0.01 nM), H874Y and wild type AR induced 2-fold greater luciferase activity than did the LNCaP mutant AR T877A. The adrenal androgen, dehydroepiandrosterone (10 and 100 nM) with H874Y stimulated a 3- to 8-fold greater response than with wild type AR and at 100 nM the response was similar with the LNCaP mutant. H874Y, like the LNCaP cell mutant, was more responsive to estradiol and progesterone than was wild type AR. The antiandrogen hydroxyflutamide (10 nM) had greater agonist activity (4- to 7-fold) with both mutant ARs than with wild type AR. AR mutations that alter ligand specificity may influence tumor progression subsequent to androgen withdrawal by making the AR more responsive to adrenal androgens or antiandrogens.
 ...
PMID:Dehydroepiandrosterone activates mutant androgen receptors expressed in the androgen-dependent human prostate cancer xenograft CWR22 and LNCaP cells. 909 97

The effect of androgen receptor transcriptional activation by RU58841, a nonsteroidal anti-androgen, was studied in the human prostate cancer PC3 cell line by cotransfection with wild-type androgen receptor (wt AR) and an androgen-responsive reporter (MMTV-ARE-CAT) construct. Anti-and rogens, hydroxyflutamide, and Casodex, and the antiestrogen, genistein, were studied in parallel for comparison with RU58841. The wt AR was activated only by the androgen dihydrotestosterone (DHT). Neither the anti-androgens nor antiestrogen can enhance AR transcriptional activity at 10(-11)-10(-7)M in PC3 cells. Hydroxyflutamide, RU58841, and Casodex, but not genistein, displayed competitively suppressive effects on DHT activation of wt AR. The potency of RU58841 was comparable to that of hydroxyflutamide. From this result, topical application of RU58841, which is considered to be a potential therapy for skin diseases, may induce systemic side effects. However, RU58841, on topical application, revealed a potent increase in density, thickening, and length of hair in the macaque model of androgenetic alopecia, whereas no systemic effects were detected. Together our results suggest that RU58841 may have potent antagonism to the wt AR and could be considered as a topically applied active anti-androgen for the treatment of androgen-dependent skin disorders, such as acne, androgenetic alopecia, and hirsutism.
 ...
PMID:Evaluation of RU58841 as an anti-androgen in prostate PC3 cells and a topical anti-alopecia agent in the bald scalp of stumptailed macaques. 979 29

Transient transfection studies have shown that the probasin (PB) promoter confers androgen selectivity over other steroid hormones, and transgenic animal studies have demonstrated that the PB promoter will target androgen, but not glucocorticoid, regulation in a prostate-specific manner. Previous PB promoters either targeted low levels of transgene expression or became too large to be conveniently used. The goal was to design a PB promoter that would be small, yet target high levels of prostate-specific transgene expression. Thus, a composite probasin promoter (ARR2PB) coupled to the bacterial chloramphenicol acetyltransferase reporter (ARR2PBCAT) was generated and tested in prostatic and nonprostatic cell lines and in a transgenic mouse model. In PC-3, LNCaP, and DU145 prostate cancer cell lines, the ARR2PB promoter gave basal expression and was induced in response to androgen and glucocorticoid treatment after cotransfection with the respective steroid receptor. Basal expression of ARR2PBCAT in the nonprostatic COS-1, MCF-7, ZR-75-1, and PANC-1 cell lines was very low; however, CAT activity could be induced in response to androgens and glucocorticoids when cells were cotransfected with either the AR or GR. In contrast to the transfection studies, ARR2PBCAT transgene expression remained highly specific for prostatic epithelium in transgenic mice. CAT activity decreased after castration, and could be induced by androgens and, in addition, glucocorticoids. This demonstrates that the necessary sequences required to target prostate-specific epithelial expression are contained within the composite ARR2PB minimal promoter, and that high transgene expression can now be regulated by both androgens and glucocorticoids. The ARR2PB promoter represents a novel glucocorticoid inducible promoter that can be used for the generation of transgenic mouse models and in viral gene therapy vectors for the treatment of prostate cancer in humans.
 ...
PMID:A small composite probasin promoter confers high levels of prostate-specific gene expression through regulation by androgens and glucocorticoids in vitro and in vivo. 1110 85

Urokinase-type plasminogen activator (u-PA) contributes to tumor progression in prostate cancer (CaP). We have previously shown that u-PA expression is upregulated through the AP-1 and PEA3 sites and repressed by androgen. However, signaling pathways mediating u-PA gene expression in CaP are not delineated. We hypothesized that MAPK pathways mediate u-PA in CaP, and thereby studied specific ERK, JNK, and P38-MAPK pathway mutant constructs and inhibitors in vitro. Human, androgen insensitive CaP PC3 cells stably transfected with the androgen receptor expression vector and vector alone were used. A u-PA promoter CAT vector transiently expressed with dominant negative mutant signaling constructs was studied. All mutants drastically reduced u-PA promoter activity. Furthermore, inhibition of PI3K, an upstream regulator in the JNK/SAPK pathway, decreased u-PA promoter transcription. Collectively, these results show that MAPK pathways ERK, JNK/SAPK, and P38-MAPK represent a significant component in the regulation of u-PA expression in human CaP.
 ...
PMID:Signal transduction-mediated regulation of urokinase gene expression in human prostate cancer. 1167 74


1 2 3 Next >>