Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0600139 (Prostate Cancer)
 4,540 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostatic carcinoma represents the second leading cause of cancer mortality in men and is responsible for over 25,000 deaths each year. Currently, no curative therapy is available for metastatic carcinoma of the prostate. The present studies were undertaken to assess the efficacy of recombinant tumor necrosis factor alpha (TNF) in the therapy of experimental prostatic carcinoma. TNF was cytotoxic to the prostate cancer cell lines PC3, DU145, and LNCAP but not benign prostatic epithelial and stromal cells in vitro. The sensitivity of the prostatic carcinoma lines to TNF-mediated cytotoxicity was enhanced by the presence of actinomycin D. Intravenous administration of TNF (50-100 micrograms/kg) to nude mice bearing subcutaneous PC3 tumors resulted in significant inhibition of primary tumor growth compared to control. TNF was also effective in reducing the growth of intraabdominal PC3 tumors induced by intrasplenic injection of PC3. Furthermore, the incidence of microscopic PC3 foci in the spleen, liver, lung, and diaphragm was diminished in mice receiving TNF therapy. These studies demonstrate the potential of TNF in the therapy of human prostatic carcinoma.
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PMID:Therapeutic efficacy of recombinant tumor necrosis factor alpha in an experimental model of human prostatic carcinoma. 231 60

The action of androgens is essential for the development of benign prostatic hyperplasia and carcinoma of the prostate. The androgen receptor is a ligand-dependent nuclear transcription factor. The transcriptional activation domain of the androgen receptor gene contains a polymorphic CAG repeat sequence. A shorter CAG repeat sequence within the normal range has been reported to be associated with increased risk of prostate cancer and symptomatic benign prostatic hyperplasia. Here, we examine the in vitro transcriptional activity of the androgen receptor (AR) with different numbers of CAG repeats within the normal range in a number of different cell lines of prostatic (LNCaP, PC3) and non-prostatic (COS-1, MCF7) origin. We utilize a luciferase reporter driven by the rat probasin promoter (-286/+28) containing two androgen receptor binding sites. Transcriptional activation of the androgen responsive reporter was observed to be greater with the AR containing 15 vs 31 CAG repeats in COS-1 cells (123.2+/-16.6 vs 78.2+/-10.9, P value 0.01) and the well differentiated prostate cancer cell line LNCaP (103.4+/-17.7 vs 81.4+/-7.7, P value 0.045). No difference was observed in the poorly differentiated prostate cancer cell line, PC3 (106.9+/-21.9 vs 109. 6+/-21.4, P>0.5) or the breast cancer cell line MCF7 (120.4+/-39.4 vs 103.1+/-23.1, P value >0.5). Dose-response experiments with varying quantities of ligand (0.01, 0.1, 1 and 10 nM dihydrotestosterone) or AR cDNA did not demonstrate significant differences in transactivation of the androgen responsive reporter in PC3 cells by the different AR constructs. This suggests that the lack of influence of CAG number in this prostatic cell line is not related to dose of ligand or quantity of androgen receptor. Western immunoblot analysis of androgen receptor protein in transiently transfected COS-1 cells did not demonstrate a difference in the expression of the androgen receptor protein with different numbers of CAG repeats following incubation in the presence or absence of androgen. Gel shift assay did not demonstrate increased DNA binding by androgen receptor with a shorter CAG repeat sequence. These experiments using a relatively androgen- and prostate-specific reporter provide evidence for an inverse relationship between androgen receptor transcriptional activity and the number of CAG repeats in the transcriptional activation domain. The effect of CAG repeat number was cell specific suggesting the involvement of accessory factors expressed differentially between different cell lines.
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PMID:Effect of the androgen receptor CAG repeat polymorphism on transcriptional activity: specificity in prostate and non-prostate cell lines. 1091 21

Bone marrow is the primary site of metastasis in patients with advanced stage prostate cancer. Prostate carcinoma cells metastasizing to bone must initially adhere to endothelial cells in the bone marrow sinusoids. In this report, we have modeled that interaction in vitro using two bone marrow endothelial cell (BMEC) lines and four prostate adenocarcinoma cell lines to investigate the adhesion mechanism. Highly metastatic PC3 and PC3M-LN4 cells were found to adhere rapidly and specifically (70-90%) to BMEC-1 and trHBMEC bone marrow endothelial cells, but not to human umbilical vein endothelial cells (15-25%). Specific adhesion to BMEC-1 and trHBMEC was dependent upon the presence of a hyaluronan (HA) pericellular matrix assembled on the prostate carcinoma cells. DU145 and LNCaP cells were only weakly adherent and retained no cell surface HA. Maximal BMEC adhesion and HA encapsulation were associated with high levels of HA synthesis by the prostate carcinoma cells. Up-regulation of HA synthase isoforms Has2 and Has3 relative to levels expressed by normal prostate corresponded to elevated HA synthesis and avid BMEC adhesion. These results support a model in which tumor cells with up-regulated HA synthase expression assemble a cell surface hyaluronan matrix that promotes adhesion to bone marrow endothelial cells. This interaction could contribute to preferential bone metastasis by prostate carcinoma cells.
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PMID:Hyaluronan synthase elevation in metastatic prostate carcinoma cells correlates with hyaluronan surface retention, a prerequisite for rapid adhesion to bone marrow endothelial cells. 1127 9

Studies on angiogenic cytokines usually are initially based upon their expression by available established cell lines. Our hypothesis is that established epithelial prostate cancer (CaP) cell lines do not accurately reflect angiogenic cytokine expression as compared to epithelial and stromal components of primary cultures generated from clinical CaP specimens. Serum free and growth factor free conditioned medium (CM) was collected from PC3, LNCaP, and their orthotopic selected prostate cancer sublines. Surgically acquired and pathologically confirmed neoplastic prostate tissue was selectively grown for selection of epithelial or stromal components, and CM was also collected. CM was assayed for urokinase (u-PA), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and tumor necrosis factor alpha (TNF-alpha). u-PA was expressed only by androgen independent cell lines, but was detectable in the epithelial and stromal cultures of androgen sensitive primary cultures. bFGF was not secreted by cell lines nor epithelial primary cultures. VEGF was universally expressed, but TNF-alpha was not secreted by cells lines nor primary cultures. These data suggest that the expression of angiogenic cytokines by established epithelial CaP cell lines does not reflect epithelial and stromal primary cultures.Prostate Cancer and Prostatic Diseases (2001) 4, 106-111
Prostate Cancer Prostatic Dis 2001
PMID:Differential expression of angiogenic cytokines by cell lines and primary cultures of human prostate cancer. 1249 47

The effects of farnesyl:protein transferase inhibitors (FTIs) were evaluated against hormone-dependent and hormone-independent prostate cancer cell lines harboring mutant and wild type Ras. The combinations of the FTI with hormones and chemotherapy were explored. The effect of FTI on the growth of human prostate cancer lines was examined under anchorage-dependent and -independent conditions. Changes in Ras processing and cellular localization were examined by immunoblotting and immunocytochemistry. Hormone-dependent (LNCaP) and -independent (TSU-Pr1, PC3 and DU145) human prostate cancer cell lines were growth-inhibited by the FTI L-744,832 at concentrations ranging from 100 nM to 20 &mgr;M. The inhibition was accompanied by loss of protein farnesylation and with the accumulation of Ha-Ras as its unprocessed, cytosolic form. No effect on N- and Ki-Ras processing was observed. The transformed phenotype of TSU-Pr1 cells, which possess a Ha-Ras Gly-12-Val activating mutation, reverted following FTI treatment. Enhanced antitumor effects were observed when the FTI was combined with gamma-radiation, etoposide, doxorubicin, cisplatin, estramustine and the antihormone bicalutamide. In particular, the combination of taxol and FTI was synergistic for DU145 cells, a cell line that is only marginally sensitive to the FTI alone. The sensitivity of human prostate cancer cell lines to the FTI is independent of the presence of mutations of tumor suppressors, cell cycle regulators and of the activation of a variety of oncogenes, including Ras. A cell line expressing mutated Ha-Ras is particularly sensitive. Enhanced antitumor effects were observed with an anti-androgen, gamma-irradiation, and several chemotherapeutic agents. These findings support the clinical evaluation of FTIs alone or in combination as treatment for this disease. Prostate Cancer and Prostatic Diseases (2001) 4, 33-43
Prostate Cancer Prostatic Dis 2001
PMID:Farnesyl:protein transferase inhibitors as potential agents for the management of human prostate cancer. 1249 61

We present the involvement and association of TNF-related apoptosis-inducing ligand (TRAIL) with apoptosis. Its potential application as a therapeutic agent in urologic oncology is discussed. We have examined the sensitivity of prostate carcinoma cell lines DU145, PC3 and LNCaP to TRAIL-induced apoptosis and the expression of TRAIL receptors. Furthermore we looked into the sensitization of those prostate carcinoma cell lines to TRAIL-mediated apoptosis by low toxic levels of actinomycin-D. Furthermore, we review and discuss the pertinent literature on the molecular biology of TRAIL, its receptors and future potential for therapy in urologic oncology. Recent discovery and characterization of TRAIL has led to further broadening and insights into the apoptotic process. Based on preceding in-vitro studies, the first in-vivo study using TRAIL has been conducted and published in 1999. Systemic application of TRAIL in severe combined immune deficient (SCID) mice resulted in tumor regression of subcutaneous implanted mammary and colon cancer and several groups are looking into TRAIL sensitivity of prostate cancer and renal cancer cellines. Our in-vitro data revealed a significant increase of apoptotic cell death rate following the combined application of TRAIL with actinomycin-D. Our results suggest that the combination of TRAIL and ActD may be a therapeutic option in the treatment of drug/hormone refractory prostate carcinoma. In the future TRAIL may be used in combination therapy with other immunotherapies or gene therapies providing a synergistic effect or enhancing the efficacy of chemotherapeutic or radiotherapeutic regimens.
Prostate Cancer Prostatic Dis 1999 Dec
PMID:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) for treatment of prostate cancer: first results and review of the literature. 1249 68

Stromal expression of some matrix metalloproteinases (MMPs) has been associated with increasing tumour burden in prostate cancer. We investigated the expression of mRNA (by RT-PCR) and protein (by zymography and western blotting) of MMPs and endogenous inhibitors (tissue inhibitors of metalloproteinases, TIMPs) in two parent epithelial prostate cancer cell lines and sublines of increasing invasive/metastatic potential. Expression of membrane type MMPs, MT1-MMP and MT3-MMP mRNA was higher in PC3-derived than in LNCaP-derived lines, whereas MT2-MMP mRNA expression was higher in the LNCaPderived than in PC3-derived cell lines. Active MT1, MT2 and MT3-MMP protein levels were similar in all lines, but processed MT-MMPs, indicative of latent MMP activation, were increased in more aggressive sublines. Expression of MMP-1, MMP-13 and TIMP-1 was higher in the more aggressive sublines and may be implicated in invasive/metastatic ability. Regulation of MMP-1 and MMP-13 expression may offer important therapeutic options for treating patients with prostate cancer.
Prostate Cancer Prostatic Dis 2003
PMID:Characterization of expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in prostate cancer cell lines. 1266 60

In a preclinical model for prostate cancer gene therapy, we have tested lentiviral vectors as a practical possibility for the transfer and long-term expression of the EGFP gene both in vitro and in vivo. The human prostate cancer cell lines DU145 and PC3 were transduced using experimental conditions which permitted analysis of the expression from a single proviral vector per cell. The transduced cells stably expressed the EGFP transgene for 4 months. After injection of the transduced cell populations into Nod-SCID mice a decrease in EGFP was only observed in a minority of cases, while the majority of tumors maintained transgene expression at in vitro levels. In vivo injection of viral vector preparations directly into pre-established subcutaneous or orthotopic tumor masses, obtained by implantation of untransduced PC3 and DU145 cells led to a high transduction efficiency. While the efficiency of direct intratumoral transduction was proportional to the dose of virus injected, the results indicated some technical limitations inherent in these approaches to prostate cancer gene therapy.
Prostate Cancer Prostatic Dis 2003
PMID:Expression of a model gene in prostate cancer cells lentivirally transduced in vitro and in vivo. 1297 Jul 26

The development of androgen-independent growth in advanced carcinoma of the prostate (CaP) is associated with poor prognosis and few therapeutic options. Chemotherapeutic drugs offer the afflicted patient palliative benefits, but these are short-lived because of the chemoresistant nature of hormone-refractory prostate cancer. Given the high percentage of CaP patients with mutations in the PTEN tumor suppressor gene, we sought to determine the involvement of the phosphatidylinositol 3'-kinase (PI3K) cascade in the development of CaP drug resistance. PTEN-negative PC3 cells were observed to have increased resistance to both doxorubicin and paclitaxel when compared with PTEN-positive DU145 cells. Furthermore, modulation of PI3K activity with the use of constitutively active and dominant-negative inhibitors was found to affect the ability to CaP cells to respond to chemotoxic treatments. Additionally, inhibition of PI3K with a small molecular weight inhibitor (LY294002) was able to potentiate the antineoplastic activity of both doxorubicin and paclitaxel in CaP cells. Interestingly, multidrug resistance protein-1 (MRP-1) expression, but not MDR-1 (p-glycoprotein), was observed to be induced as a consequence of PI3K activation in these cell types. Inhibition of MRP-1 expression via siRNA was observed to synergistically sensitize CaP cells to chemotoxic drugs while having no appreciable effect on cell growth in the absence of these compounds. Taken together, these data suggest that PI3K activation can lead to the development of chemoresistant cells in prostatic carcinomas through the up-regulation of MRP-1. Thus, inhibition of PI3K activity with concomitant administration of chemotoxic compounds may prove beneficial in preventing the development of drug resistance in patients with hormone-refractory prostate cancer.
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PMID:Phosphatidylinositol 3'-kinase activation leads to multidrug resistance protein-1 expression and subsequent chemoresistance in advanced prostate cancer cells. 1554 10

Epidemiologic studies have demonstrated an inverse association between flavonoid intake and prostate cancer (PCa) risk. The East Asian diet is very high in flavonoids and, correspondingly, men in China and Japan have the lowest incidence of PCa worldwide. There are thousands of different naturally occurring and synthetic flavonoids. However, only a few have been studied in PCa. Our aim was to identify novel flavonoids with antiproliferative effect in PCa cell lines, as well as determine their effects on cell cycle. We have screened a representative subgroup of 26 flavonoids for antiproliferative effect on the human PCa (LNCaP and PC3), breast cancer (MCF-7), and normal prostate stromal cell lines (PrSC). Using a fluorescence-based cell proliferation assay (Cyquant), we have identified five flavonoids, including the novel compounds 2,2'-dihydroxychalcone and fisetin, with antiproliferative and cell cycle arresting properties in human PCa in vitro. Most of the flavonoids tested exerted antiproliferative effect at lower doses in the PCa cell lines compared to the non-PCa cells. Flow cytometry was used as a means to determine the effects on cell cycle. PC3 cells were arrested in G2/M phase by flavonoids. LNCaP cells demonstrated different cell cycle profiles. Further studies are warranted to determine the molecular mechanism of action of 2,2'-DHC and fisetin in PCa, and to establish their effectiveness in vivo.
Prostate Cancer Prostatic Dis 2006
PMID:Novel antiproliferative flavonoids induce cell cycle arrest in human prostate cancer cell lines. 1631 91


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