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

The binding of 3H-R 1881 to cytosol prepared from benign and malignant prostatic neoplasms has been investigated. We have demonstrated that high affinity binding of 3H-R 1881 is present in cytosol preparations of benign prostatic hyperplasia, in specimens of prostatic cancer obtained from patients prior to hormonal therapy and in carcinoma of the prostate metastatic to lymph nodes. In addition, high affinity binding was present in all specimens of prostatic cancer from patients who had objective evidence of progressive metastatic disease after an initial response to hormonal therapy. Until greater numbers of patients have been studied the significance of these findings can only be speculative. Because the binding of 3H-R 1881 may measure androgen and progesterone receptors future investigations must include careful steroid specificity studies. Finally, because steroidal hormones exert their major influence within the nucleus of target tissues the measurement of nuclear receptor content may provide a more accurate means to predict the hormonal responsiveness of prostatic cancer.
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PMID:The binding of a potent synthetic androgen--methyltrienolone (R 1881)--to cytosol preparations of human prostatic cancer. 8 28

To facilitate an understanding of how androgens participate in the genesis of human benign hyperplasia and carcinoma we assayed androgen receptor in the epithelium and stroma of human prostatic tissue from 57 patients. Immunohistochemical staining of human androgen receptor was performed on 106 sections of normal prostate, benign prostatic hyperplasia (BPH) and prostate cancer. To determine variability of androgen receptor staining sections taken from different portions of the gland were studied. Frozen tissue sections were incubated with monoclonal antiandrogen receptor antibodies and staining was completed by the indirect avidin-biotin peroxidase method. Antibody staining was found mainly in the nucleus of prostatic epithelial cells, although some stromal cells also showed positive staining. Unlike normal prostate, there was a heterogeneous distribution of androgen receptor in BPH and prostate cancer. The androgen receptor content in well differentiated adenocarcinoma epithelium was significantly higher compared to moderately (p less than 0.05) and poorly (p less than 0.05) differentiated adenocarcinoma. Regardless of the origin of stromal tissue, some staining was observed. In each specimen studied the androgen receptor staining was consistent qualitatively and quantitatively for each pathological component throughout the specimen. These data confirm that androgen receptor is a nuclear receptor protein. Furthermore, they show the ability of monoclonal antibodies to reveal cellular/subcellular distribution of androgen receptor, and demonstrate a correlation between the degree of tumor differentiation and androgen receptor content in epithelial but not in stromal cells. These observations may have important implications for understanding the variable tumor response to hormone therapy.
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PMID:Nuclear localization of androgen receptor in heterogeneous samples of normal, hyperplastic and neoplastic human prostate. 137 52

The authors investigated the ability of androgen receptor binding in prostate cancer tissue to predict the response of prostate cancer patients to endocrine therapy. The clinical response of 37 previously untreated patients with various grades and stages of prostate cancer was correlated with androgen receptor binding and detailed histologic data obtained before treatment. All patients underwent cold-punch transurethral resection of the prostate and received endocrine therapy. The association between time to progression and cytosolic androgen binding was not significant. However, the associations of time to progression to nuclear binding and to total androgen binding were significant (P = 0.029 and 0.038, respectively). The authors found no association between clinical stage and time to progression, but did find an association between time to progression and pathologic grade (P = 0.003); grade 4 lesions were the least responsive to hormone therapy. When grade 4 lesions were excluded (N = 3), binding levels were still predictive of progression independently of grade and stage. The authors conclude that nuclear receptor binding activity in localized and metastatic prostate cancer tissue is predictive of response to hormonal manipulation.
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PMID:Relationship between androgen receptor binding activity in human prostate cancer and clinical response to endocrine therapy. 382 60

Cytoplasmic and nuclear receptor sites of the prostate will be determined for a qualitative information about the pattern of specific bindings. Their qualitative evaluation and their selective suppression will give an idea about the hormonal influence and regulation in prostatic tissue. These investigations are performed in some cases of prostatic cancer. The difficulty of tissue preparation is caused by the individual distribution of collagen tissue in prostatic cancer which will decide the yield of purified receptor sites. Besides the elemination of unspecific binding sites like SHBG and albumin is an evidence for the value of a method. According to high amount of binding sites the most effective preparation of patients before a tissue biopsy is discussed. For the clinical application the DCC test in case of cytoplasmic sites and the exchange test for nuclear sites seem to provide a suitable method. Performing gelfiltration and additional test with denatured material is necessary because of the similar size of SHBG and receptor complexes interfering the results.
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PMID:[Possibilities for the evaluation of receptor sites in benign prostatic hyperplasia and carcinoma of the prostate (author's transl)]. 616 65

To assess whether pre-treatment prostatic androgen receptor measurements would be of value in predicting the response to hormonal therapy in patients with prostatic cancer 23 men with metastatic carcinoma of the prostate underwent prostatic biopsy before treatment. Cytosolic and nuclear prostatic androgen receptor contents were measured by a single saturating dose, dextran-charcoal assay. All patients had measurable levels of androgen receptor in prostatic tissue and all demonstrated objective evidence of improvement following hormonal therapy. Thus, if androgen receptor measurements are to be useful in predicting prognosis correlations between quantitative levels of receptor and quantitative aspects of response must be established. In our study response was quantitated by measuring the duration of response and survival following hormonal treatment. The strong correlation between duration of response and survival (p less than 0.01) demonstrated herein suggests that survival in these patients is related directly to the duration of time patients respond to hormonal therapy. Neither total cellular nor cytosolic androgen receptor content correlated with response. However, nuclear androgen receptor content correlated with the duration of response and survival following hormonal treatment (p less than 0.05). Furthermore, in patients with nuclear receptor levels less than 110 fmol. per mg. deoxyribonucleic acid the duration of response (7.1 plus or minus 3.8 months) and survival (14.4 plus or minus 5.9 months) was significantly shorter than in patients with higher levels of nuclear receptor (17.3 plus or minus 10.4 and 24.7 plus or minus 8.8 months, respectively) (p less than 0.05). These findings, which are the first report of a correlation between nuclear androgen receptor content and hormonal responsiveness, suggest that measurements of nuclear receptor may aid in identifying those patients unlikely to obtain a prolonged response from hormonal therapy.
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PMID:Correlation of prostatic nuclear androgen receptor content with duration of response and survival following hormonal therapy in advanced prostatic cancer. 706 20

The purpose of this study was to examine the effects of 13-cis-retinoic acid (13-cis-RA) on the growth regulation of DU-145 human prostatic cancer cells. The results of these experiments demonstrate that cell growth and metastatic potential of DU-145 cells were significantly inhibited by 13-cis-RA (10 microM). In order to elucidate the possible molecular mechanisms of 13-cis-RA action on prostate cancer cells, we examined the expression of nuclear receptor genes (hRXR alpha) and found that 13-cis-RA treated cells showed higher mRNA expression for hRXR alpha nuclear receptors compared to untreated cells. To elucidate further the possible biochemical mechanisms associated with these alterations, we analyzed the phosphorous metabolites by MR spectroscopy and found that the major metabolites were PME, (PC, PE) and DPDE (UDP-GalNAc, UDP-GLcNAc). The DU-145 cells and xenografts, which were both treated with 13-cis-RA, showed a two-fold decrease in DPDE's, compared to their controls. The higher resolution spectra of perfused cells revealed that phosphocholine levels were twice as high in 13-cis-RA-treated DU-145 cells as compared to untreated cells. These investigations demonstrate for the first time that 13-cis-RA inhibits the growth of human prostatic cancer cells, and this inhibition is associated with an increase in hRXR alpha nuclear receptor gene expression and alterations in phosphorous metabolites detected by 31P MR spectroscopy.
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PMID:13-cis-retinoic acid-mediated growth inhibition of DU-145 human prostate cancer cells. 801 74

The refractoriness of prostate cancer to androgen suppression is the landmark of clinically aggressive disease. In this study, the androgen-dependent LNCaP prostate cancer cells were transfected with the mutated c-Ha-ras gene from the T24 human bladder cancer. The derivative clone overexpressing T24-ras (LNCaP(T24-ras)) proliferated in androgen-depleted medium and showed increased growth. Protein isoprenylation and p21ras farnesylation in LNCaP(T24-ras) cells were tested in the presence of phenylacetate to document a possible relationship with the drug-induced inhibition of cell proliferation. Phenylacetate is a differentiation inducer that down-regulates in vitro the expression of the myc oncogene and activates the human peroxisome proliferator-activated nuclear receptor involved in cell growth regulation. The drug inhibited protein isoprenylation and p21ras farnesylation in LNCaP(T24-ras) cells; IC50 values were 3.1 and 3.3 mM, respectively, compared with controls. The drug reduced the cellular levels of endogenous farnesyl-PP (mean IC50 = 3.5 mM) and inhibited activation of the p21ras downstream target, p42(MAPK)/ERK2. LNCaP(T24-ras) was more sensitive than the parental line to both growth inhibition (mean IC50 = 3.01 and 7.1 mM, respectively) and apoptosis by phenylacetate. Exogenous farnesyl- and geranylgeranyl-PP indeed reduced the effects of the drug on proliferation and apoptosis in LNCaP(T24-ras) cells. In conclusion, the inhibition of protein isoprenylation and p21ras farnesylation by phenylacetate resulted in increased chemosensitivity of the androgen-independent LNCaP(T24-ras) cells compared with LNCaP, and this effect might contribute to the pharmacological activity of the drug.
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PMID:Phenylacetate inhibits protein isoprenylation and growth of the androgen-independent LNCaP prostate cancer cells transfected with the T24 Ha-ras oncogene. 864 57

The androgen receptor (AR) is a structurally conserved member of the nuclear receptor superfamily. The amino-terminal domain is required for transcriptional activation and contains a region of polyglutamine encoded by CAG trinucleotide repeats. In humans, the number of CAG repeats is polymorphic; the average number is 22 in Caucasian males. Expansion of CAG repeats in the AR has clinical implications for human disease. As androgen influences prostate cancer growth, polymorphisms in CAG repeat length may affect the clinical course of patients with prostate cancer. To test for an association between clinical parameters of human prostate cancer and CAG repeat length, we analyzed normal lymphocyte DNA from 109 patients. The CAG region of the AR was amplified by the PCR. Reaction products were then amplified using end-labeled internal primers, cut at the internal PstI site and assayed on sequencing gels using a sequence ladder as a size standard. Sequence analysis of several samples validated this method for measurement of CAG repeat number. The median age of patients was 63 yr (range, 42-83), with 104 Caucasian, 2 African American, 1 Asian, and 2 other racial origin. The median repeat length was 25 for patients with stage A, 22 for patients with stage B, 22 for patients with stage C, and 23 for patients presenting with stage D disease. A significant correlation between CAG repeat length and age at onset was observed, whereas correlations with stage, level of prostate-specific antigen at diagnosis, and time to prostate-specific antigen relapse were not significant. Shorter CAG repeat lengths may be associated with the development of prostate cancer in men at a younger age. These data suggest that CAG repeat length can affect the risk of developing prostate cancer.
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PMID:Androgen receptor CAG repeat lengths in prostate cancer: correlation with age of onset. 895 49

Androgens mediate a number of diverse responses through the androgen receptor, a 110 kD ligand-activated nuclear receptor. Androgen receptor expression, which is found in a variety of tissues, changes throughout development, aging, and malignant transformation. The androgen receptor can be activated by two ligands, testosterone and dihydrotestosterone, which bind to the androgen receptor with different affinities. This difference in binding affinity results in different levels of activation of the androgen receptor by the two ligands. The androgen receptor acts as a transcriptional modifier of a variety of genes by binding to an androgen response element. The ability to confer androgen specific actions by the androgen response element may depend on other cell-specific transcription factors and cis-acting DNA elements in close proximity to it. Testosterone and dihydrotestosterone appear to act upon an identical nuclear receptor. However, in certain instances, they mediate different physiologic responses. For example, dihydrotestosterone, but not testosterone, is capable of mediating full sexual development of the male external genitalia. In some cases, the androgen receptor may induce opposite physiologic responses in similar tissue types depending on their location. For example, in male pattern baldness, activated androgen receptors may suppress the growth of distinct hair follicle populations through initiating stromal-epithelial actions, whereas other hair follicles continue to proliferate. In other cases, altered androgen receptor activity due to its mutation or altered expression may lead to pathology such as recurrence of prostate cancer due to development of androgen independence allowing tumor cell proliferation under androgen deprivation.
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PMID:The androgen receptor: a mediator of diverse responses. 915 12

The seco-steroid hormone, 1 alpha, 25 dihydroxyvitamin D3 (1 alpha,25(OH)2D3) binds to a specific nuclear receptor that acts as a ligand-inducible transcription factor. The resulting genomic effects include partial arrest in G0/G1 of the cell cycle and induction of differentiation; these effects have been observed in various types of cancer. Recently, we produced enzymatically the natural 24-oxo metabolites of 1 alpha,25(OH)2D3 and two of its potent synthetic analogs (1 alpha,25-(OH)2-16-ene-D3 and 1 alpha,25-(OH)2-20-epi-D3) using a rat kidney perfusion system. We have found that the 24-oxo metabolites of both 1 alpha,25(OH)2D3 and its analogs have either the same or greater antiproliferative activity against various cancer cells as their parental compounds. Notably, two cell lines (DU-145 (prostate cancer) and MDA-MB-436 [breast cancer]) that were extremely resistant to the antiproliferative effects of vitamin D3 analogs displayed greater sensitivity towards the 24-oxo metabolite of the vitamin D3 analog. Similarly, the 24-oxo metabolites had the capacity to induce differentiation and apoptosis and to diminish the proportion of cells in S phase. Most interestingly, while the analog 1 alpha,25(OH)2-20-epi-D3 induced expression of BRCA1 in MCF-7 breast cancer cells; its 24-oxo metabolite dramatically suppressed BRAC1 expression. Thus, we have shown for the first time that the various biological activities produced by the hormone 1 alpha,25(OH)2D3 and some of its analogs may represent a combination of actions by the hormone 1 alpha,25(OH)2D3 and its natural 24-oxo metabolites.
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PMID:Vitamin D3 analogs and their 24-oxo metabolites equally inhibit clonal proliferation of a variety of cancer cells but have differing molecular effects. 925 97


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