UMLS:C0376358 - FACTA Search

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)

The molecular mechanism of androgen-independent growth of prostate cancer after androgen ablation was explored in LNCaP cells. An androgen-dependent clonal subline of the LNCaP human prostate carcinoma cell line, LNCaP 104-S, progressed to a slow growing stage (104-R1) and then to a faster growing stage (104-R2) during more than 2 yr of continuous culture in the absence of androgen. Androgen-induced proliferation of 104-S cells is inhibited by the antiandrogen Casodex, while proliferation of 104-R1 and 104-R2 cells is unaffected by Casodex. This indicates that proliferation of 104-R1 and 104-R2 cells is not supported by low levels of androgen in the culture medium. Compared with LNCaP 104-S cells, both 104-R1 and 104-R2 cells express higher basal levels of androgen receptor (AR), and proliferation of these two cell lines is paradoxically repressed by androgen. After continuous passage in androgen-containing medium, 104-R1 cells reverted back to an androgen-dependent phenotype. The mechanism of androgenic repression of 104-R1 and 104-R2 sublines was further evaluated by examining the role of critical regulatory factors involved in the control of cell cycle progression. At concentrations that repressed growth, androgen transiently induced the expression of the cyclin-dependent kinase (cdk) inhibitor p21waf1/cip1 in 104-R1 cells, while expression of the cdk inhibitor p27Kip1 was persistently induced by androgen in both 104-R1 and 104-R2 cells. Induced expression of murine p27Kip1 in 104-R2 cells resulted in G1 arrest. Specific immunoprecipitates of Cdk2 but not Cdk4 from androgen-treated 104-R1 cells contained both p21waf1/cip1 and p27Kip1. This observation was confirmed by in vitro assay of histone H1 and Rb (retinoblastoma protein) phosphorylation by the proteins associated with the immune complex. Furthermore, inhibition of Cdk2 activity correlated with the accumulation of p27Kip1 and not p21waf1/cip1. From these results we conclude that androgenic repression of LNCaP 104-R1 and 104-R2 cell proliferation is due to the induction of p27Kip1, which in turn inhibits Cdk2, a factor critical for cell cycle progression and proliferation.
...
PMID:Progression of LNCaP prostate tumor cells during androgen deprivation: hormone-independent growth, repression of proliferation by androgen, and role for p27Kip1 in androgen-induced cell cycle arrest. 965 99

Whether androgen regulates the proliferation and survival of androgen-responsive prostate cancer cells directly or indirectly via a paracrine pathway initiated in androgen receptor (AR)-expressing stromal cells is unknown. To resolve this issue, female mice heterozygous for the testicular feminized male loss of function mutation in their X-linked AR genes were cross-bred to T cell-defective homozygous male nude mice. Using a PCR-based restriction enzyme digestion method, the resulting AR/tfm, Nu/nu F1 hybrid females were identified and back-crossed to homozygous male nude mice to produce AR-null male nude mice lacking both AR and T-cell function. Androgen-responsive PC-82 human prostate cancers were xenografted into these AR-null versus AR-wild-type male nude mice. In both backgrounds, the cancer cells did not grow in nonandrogenized hosts. In contrast, PC-82 prostate cancer cells grew with identical characteristics (i.e., take rate, morphology, PSA expression, growth rate, and percentage of cell proliferating or dying) in androgenized hosts of both backgrounds. Likewise, in both backgrounds, androgen ablation of mice bearing growing PC-82 cancers resulted in the inhibition of proliferation and activation of programmed (apoptotic) cell death of the cancer cells. These results demonstrate that both the androgen-stimulated proliferation and the suppression of programmed cell death of PC-82 human prostate cancer cells are initiated by the AR pathway directly within these cancer cells themselves and do not involve initiation by AR-expressing stromal cells in a paracrine manner.
...
PMID:Development of an androgen receptor-null model for identifying the initiation site for androgen stimulation of proliferation and suppression of programmed (apoptotic) death of PC-82 human prostate cancer cells. 969 59

Androgen receptor (AR) plays a key role in cell growth both in the normal prostate and in prostate cancer. Androgen ablation and prolonged antiandrogen therapy can give rise to AR-dependent prostate tumors, which nonetheless can grow in the androgen-deprived milieu. Here we describe the ribozyme approach to selectively degrading the AR mRNA and thereby inhibiting AR function. A trans-acting hammerhead ribozyme was designed to cleave the rat AR mRNA at the position +1827/ 1828, a region predicted to be minimally involved in generating stable secondary structures. Using AR mRNA fragments as substrates, it was established that this ribozyme can specifically cleave the RNA target in a sequence-specific manner. Kinetic experiments determined a Km for the substrate of 77 nM and a kcat/Km value of 1.8 x 10(7) M(-1) x min(-1), suggesting a catalytic efficiency similar to that of protein enzymes such as the relatively nonspecific ribonuclease A and a sequence-specific endonuclease EcoRI. Transient cotransfections of prostate-derived PC3 cells with three plasmids, an AR-inducible chloramphenicol acetyltransferase (CAT) reporter, an AR expression vector, and a ribozyme expression vector, showed that the ribozyme was capable of reducing the functional activity of AR. At an equimolar ratio of the AR expression plasmid to ribozyme expression plasmid, androgen-inducible CAT activity was inhibited 70%. Similar extents of inhibition were also observed at the cellular mRNA level using ribonuclease protection assays, indicating that the ribozyme functioned as an AR mRNA cleaving enzyme in cellulo. Immunocytochemical examination revealed a decline of AR immunoreactivity in ribozyme-transfected cells. In addition, no morphologically detectable cellular abnormalities were associated with ribozyme expression, indicating the absence of deleterious side effects. These results offer a new avenue for the control of AR function and cell growth, especially in the case of androgen-resistant, but AR-dependent, prostate cancer cells.
...
PMID:Catalytic cleavage of the androgen receptor messenger RNA and functional inhibition of androgen receptor activity by a hammerhead ribozyme. 977 79

Cancer of the prostate is an heterogenic, "epidemic" world-wide tumor, which represents the most common form of solid cancer in adult males, excluding nonmelanoma skin cancer. Prostate cancer now surpasses the incidence of lung cancer and becomes the second leading cause of male cancer death in the industrialized West countries. The incidence and mortality of prostate cancer are increasing to alarming rates (in the USA carcinoma prostate was projected to be responsible for 14% of all male cancer deaths in 1996). As the life expectancy of the male population increases over time, the incidence of clinical prostate cancer will also increase. There is a wide geographic variation in the incidence of clinical prostate cancer, with higher rates in the United States than in China. A difference in diagnostic practice with regard to prostate cancer can be the explanation for this wide divergence. One risk factor which could explain this fact is the high fat Western diet. It is also apparent that prostate cancer is now being detected at less advanced stages than in the past. It has become evident that there is a greater than expected incidence of this tumor in the male relatives of men who died from the disease. Hereditary prostate cancer is characterized by Mendelian autosomal dominant inheritance, and an early onset of the disease. Prostate specific antigen (PSA) represents the best serum marker for prostatic carcinoma and is considered as most perfect tumor marker available today. Nevertheless, the use of PSA to detect prostate cancer is clinically imprecise since benign and malignant prostate disease can cause elevations in PSA. The biological behaviour and the natural course of prostate cancer are poorly understood. There are far larger numbers of males who have a so-called latent, well-differentiated microscopic (clinically insignificant) prostate carcinoma that may never progress to invasive clinical disease with metastatic potential. These incidental cancers discovered histologically after the transurethral or open prostatectomy and as a result of the prostate biopsy in patients with the high level of PSA are currently not well understood. Results of the mass screening for prostate cancer are at present controversial and their benefit is still not confirmed. There is now strong evidence for the screening of first degree male relatives of men with prostate cancer, particularly male relatives of those developing the disease at a young age and those with a strong positive family history of the disease. There is no debate that the earlier diagnosis of prostate carcinoma, especially in young men give them the best chance to be cured. The "watchful waiting" seems the best treatment strategy for older men with so called insignificant carcinoma. The aggressive modalities of the therapy--radical prostatectomy, radiation therapy, interstitial brachy-therapy or interstitial cryotherapy--are the curable methods only for organ-confirmed tumors and advocated in patients with life expectancy longer than 10 years. Androgen ablation therapy is the treatment of choice for the palliation of patients with advanced prostate cancer. Maximal androgen ablation (combination of medical or surgical castration and an antiandrogen) has been shown to increase the survival of patients with metastatic prostate cancer. As the incidence and prevalence of prostate cancer have increased, so has mortality, though at a slower rate. This fact may more a reflection of earlier diagnosis rather than improvements in treatment. Five-year prostate cancer survival has improved for every stages of disease in the last decenium. Thanks to the screening programmes performed in many countries, urologists are faced with an increasing incidence of clinical less advanced prostate cancer and this trend is likely to continue. (ABSTRACT TRUNCATED)
...
PMID:[Adenocarcinoma of the prostate]. 978 3

In previous studies, we have demonstrated that androgen ablation-induced growth inhibition of androgen-responsive PC-82 and A-2 human prostate cancer xenografts involves not only direct activation of programmed (apoptotic) death of these cells but also indirect activation of this death process via a decrease in tumor angiogenesis secondary to a reduction in tumor vascular endothelial growth factor (VEGF) levels. To determine whether androgens consistently regulate angiogenesis via control of VEGF levels, an additional human (i.e., LnCaP) and two rodent (i.e., Dunning G and H) androgen-sensitive prostate cancer sublines were tested. Androgen ablation causes a decrease in the subsequent growth rate of each of these three additional prostate cancer sublines, and this growth inhibition is consistently associated with a >60% reduction in tumor VEGF levels. To examine whether androgens regulate VEGF levels not only in malignant but also in normal prostatic tissue, male rats were castrated, and the temporal changes in the VEGF content of ventral prostate tissue were determined. One week after castration, VEGF content decreased to <20% within the ventral prostate. Subsequent replacement with exogenous androgen to long-term castrated rats stimulated an 8-fold rise in ventral prostate VEGF content within 1 week. To evaluate whether androgen regulation of VEGF is due to a direct effect of androgen on prostatic cells, the dose-response ability of androgens to increase VEGF levels in media of LnCaP cells grown in vitro was tested. These studies demonstrate that androgens directly stimulate VEGF secretion in these cells. The presence of 4-5-fold higher levels of VEGF in prostatic fluid versus seminal vesicle fluid obtained from benign prostatic hyperplasia and clinically localized prostate cancer patients suggests that elevated levels of VEGF may contribute to the progression of these prostatic conditions by promoting angiogenesis. In summary, one of the mechanisms for androgen sensitivity for the control of the growth of both normal and malignant prostatic tissue is via its stimulation of VEGF levels.
...
PMID:Androgens regulate vascular endothelial growth factor content in normal and malignant prostatic tissue. 981 54

Androgen ablation has been an effective treatment in patients with advanced prostate cancer. However, most treated patients develop hormonally resistant disease and do not respond to conventional chemotherapy. Immunotherapy against prostate cancer is an alternative approach in overcoming hormonal/drug-resistant prostate cancer. Cytotoxic immune lymphocytes kill target cells via the perforin/granzyme and the Fas-ligand (Fas-L) pathways. We hypothesize that tumor cells respond poorly to immunotherapy by developing resistance to killing by the Fas-L mechanism. This study investigated whether prostate tumor cells are sensitive to Fas-mediated killing. The human prostate carcinoma cell lines DU145, PC-3, and LnCAP were examined for their sensitivity to killing and apoptosis by the Fas-L agonist anti-Fas antibody and CTLs. All three lines moderately expressed the Fas antigen on the cell surface; however, all three lines were relatively resistant to cytotoxicity mediated by anti-Fas (CH-11) antibody. Pretreatment of DU145 and PC-3 with subtoxic concentrations of drugs followed by anti-Fas antibody resulted in synergistic cytotoxicity and apoptosis, whereas only an additive effect was obtained with LnCAP. Chemosensitization with drugs and anti-Fas was completely blocked by the addition of neutralizing anti-Fas antibody. The murine CTL hybridoma, PMMI, which kills only via the Fas-L pathway, was able to kill chemosensitized PC-3 and DU145 but not LnCAP cells. Furthermore, this cytotoxicity was blocked by anti-Fas neutralizing antibody. Chemosensitization of PC-3 and DU145 prostate tumor cells was not due to up-regulation of Fas-receptor antigen expression. Treatment of tumor cells with cisplatin did not down-regulate the antiapoptotic genes bcl-2, FAP-1, and c-myc. Further, there was no induction by cisplatin of Fas-L on the tumor cells, thus ruling out Fas/Fas-L-mediated autologous killing. These findings demonstrate that pretreatment of drug-resistant/CTL-resistant prostate DU145 and PC-3 tumor cells with subtoxic concentrations of certain chemotherapeutic drugs sensitizes the tumor cells to Fas-mediated cytotoxicity. These findings suggest that chemosensitization of tumor cells should optimize the response to immunotherapeutic interventions in the treatment of hormone-resistant/drug-resistant prostate cancer.
...
PMID:Chemosensitization of human prostate carcinoma cell lines to anti-fas-mediated cytotoxicity and apoptosis. 981 72

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.
...
PMID:Methylation of the androgen receptor promoter CpG island is associated with loss of androgen receptor expression in prostate cancer cells. 985 55

Androgen-independent growth of prostate cancer is correlated with expression of bcl-2. The impact of bcl-2 expression on the growth of prostate cancer cells following androgen ablation, was examined in the androgen-sensitive prostatic carcinoma cell line, LNCaP. Vector control and bcl-2 expressing LNCaP cells were grown subcutaneously in male nude mice. Tumor volume, apoptosis, and proliferation were assessed following castration. The levels of c-myc, p53, p21, bax, and bcl-2 protein were assessed by Western blotting. Bcl-2 expressing tumors exhibited a significant augmentation in growth compared to controls (p 0.01). No difference in the spontaneous rate of proliferation was observed between bcl-2 and control tumors, however, bcl-2 expressing tumors exhibited lower rates of apoptosis. Following orchiectomy the apoptotic index remained significantly lower in bcl-2 expressing tumors (p 0.002 at day 3). The proliferative index was maintained in bcl-2 expressing, but not control tumors following castration. This resulted in a significant growth advantage in bcl-2 tumors subsequent to androgen ablation (p 0.001). These changes were accompanied by alterations in the levels of gene products known to regulate the cell cycle and/or apoptosis. These results emphasize the significance of bcl-2 expression during prostate cancer progression and suggest possible mechanisms for the acquisition of androgen-independent tumor growth.
...
PMID:Molecular correlates of bcl-2-enhanced growth following androgen-ablation in prostate carcinoma cells in vivo. 985 30

Androgen deprivation therapy is the most effective systemic treatment for advanced prostate cancer. However, as most patients who die from prostate cancer have hormone refractory disease, fine tuning of antiandrogen treatment by combined androgen blockade (CAB) can not be expected to improve survival significantly. Only the South West Oncology Intergroup (SWOG) study 0036 has shown a significant advantage for CAB compared with luteinizing hormone-releasing hormone (LH-RH) agonist alone. However, the results of this study should be interpreted with caution as the patients had to self-administer their treatment by daily injection so compliance may not have been optimal. Also, those receiving LH-RH agonist alone were not covered against disease flare. Indeed, no trial using depot LH-RH agonist with or without flutamide has been able to show a survival benefit. When treatment with LH-RH agonist plus antiandrogen was compared with orchiectomy alone, only the European Organization for Research and Treatment of Cancer (EORTC) study 30,853 showed a significant difference in favour of CAB. However, in this study an increased proportion of patients receiving CAB may have had a more favourable prognosis. Only one study comparing orchiectomy plus antiandrogen with orchiectomy alone has shown an advantage for CAB therapy, and this was only slight. Therefore, as yet there is no justification for long-term use of CAB. However, short-term antiandrogen treatment must be used to prevent disease flare during initiation of LH-RH agonist treatment.
...
PMID:Arguments against the long-term use of combined androgen blockade. 985 93

Objectives: Long-term results of radiotherapy in locally advanced prostate cancer are poor due to local and distant failures. Since prostate cancer is hormone dependent, tumor androgen deprivation may enhance tumor eradication. Methods: Three randomized phase III trials, RTOG and EORTC are reported: they assess androgen suppression by using a luteinizing hormone-releasing hormone analogue (LH-RHa) with or without androgen blockade before and during, or during and after external irradiation. Results: A gain in disease-free, local relapse-free and metastasis-free survival has been obtained (p < 0.001). Only the EORTC 22863 trial has reported a significant improvement in overall survival (p = 0.001) with an LH-RHa started the first day of radiotherapy and administered every 4 weeks over 3 years. In the RTOG 85-10 trial, and LH-RHa, initiated in the last week of radiation therapy and continued until relapse, increased overall survival only in patients with poorly differentiated tumor with a Gleason score of 8-10 (p = 0.03). Conclusion: Androgen suppression prior to and during radiation improves disease-free survival; adjuvant hormonal therapy with an LH-RHa during and after radiation improves overall survival.
...
PMID:Adjuvant Hormonal Treatment with Radiotherapy for Locally Advanced Prostate Cancer. 985 48

<< Previous 1 2 3 4 5 6 7 8 9 10