Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q04609 (prostate-specific membrane antigen)
 1,287 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to provoke an immune response, a tumor vaccine should not only maximize antigen-specific signals, but should also provide the necessary "co-stimulatory" environment. One approach is to genetically manipulate tumor cells to either secrete lymphokines (GM-CSF, IL-12, IL-15) or express membrane bound molecules (CD80, CD86). Furthermore, patient dendritic cells can be loaded with tumor-associated antigens or peptides derived from them and used for immunotherapy. Genetic modification of dendritic cells can also lead to presentation of tumor-associated antigens. Transfection of dendritic cells with DNA encoding for such antigens can be done in vitro, but transfection efficiency has been uniformly low. Alternatively, dendritic cells can also be modulated directly in vivo either by "naked" DNA immunization or by injecting replication-deficient viral vectors that carry the tumor specific DNA. Naked DNA immunization offers several potential advantages over viral mediated transduction. Among these are the inexpensive production and the inherent safety of plasmid vectors, as well as the lack of immune responses against the carrier. The use of viral vectors enhances the immunogenicity of the vaccine due to the adjuvant properties of some of the viral products. Recent studies have suggested that the best strategy for achieving an intense immune response may be priming with naked DNA followed by boosting with a viral vector. We have successfully completed a phase I and phase II clinical trials on immunotherapy of prostate cancer using naked DNA and adenoviral immunizations against the prostate-specific membrane antigen (PSMA) and phase I clinical trial on colorectal cancer using naked DNA immunization against the carcinoembryonic antigen (CEA). The vaccination was tolerated well and no side effects have been observed so far. The therapy has proven to be effective in a number of patients treated solely by immunizations. The success of the treatment clearly depends on the stage of the disease proving to be most efficient in patients with minimal disease or no metastases. A panel of changes in the phenotype of peripheral blood lymphocytes and the expression of intra-T-cell lymphokines seems to correlate with clinical improvement.
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PMID:In vivo transfection and/or cross-priming of dendritic cells following DNA and adenoviral immunizations for immunotherapy of cancer--changes in peripheral mononuclear subsets and intracellular IL-4 and IFN-gamma lymphokine profile. 1141 9

To identify genes that are differentially up-regulated in prostate cancer of transgenic adenocarcinoma mouse prostate (TRAMP) mice, we subtracted cDNA isolated from mouse kidney and spleen from cDNA isolated from TRAMP-C1 cells, a prostate tumor cell line derived from a TRAMP mouse. Using this strategy, cDNA clones that were homologous to human six-transmembrane epithelial antigen of the prostate (STEAP) and prostate stem cell antigen (PSCA) were isolated. Mouse STEAP (mSteap) is 80% homologous to human STEAP at both the nucleotide and amino acid levels and contains six potential membrane-spanning regions similar to human STEAP. Mouse PSCA (mPsca) shares 65% homology with human PSCA at the nucleotide and amino acid levels. mRNA expression of mSteap and mPsca is largely prostate-specific and highly detected in primary prostate tumors and metastases of TRAMP mice. Both mSteap and mPsca map to chromosome 5. Another known gene coding for mouse prostate-specific membrane antigen (mPsma) is also highly expressed in both primary and metastatic lesions of TRAMP mice. These results indicate that the TRAMP mouse model can be used to effectively identify genes homologous to human prostate-specific genes, thereby allowing for the investigation of their functional roles in prostate cancer. mSteap, mPsca, and mPsma constitute new tools for preventative and/or therapeutic vaccine construction and immune monitoring in the TRAMP mouse model that may provide insights into the treatment of human prostate cancer.
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PMID:Murine six-transmembrane epithelial antigen of the prostate, prostate stem cell antigen, and prostate-specific membrane antigen: prostate-specific cell-surface antigens highly expressed in prostate cancer of transgenic adenocarcinoma mouse prostate mice. 1147 26

Prostate-specific membrane antigen (PSMA) is a type-2 membrane protein expressed in the prostate, and it is highly expressed in metastatic or poorly differentiated adenocarcinomas. Moreover, PSMA expression is upregulated by androgen deprivation. These advantages make PSMA a useful target for prostate cancer therapy, especially in combination with conventional hormonal treatment. We recently reported that a prostate-specific enhancer is present in the third intron of the PSMA gene. In this study, we have further analyzed the activity of PSMA promoter/enhancer in prostate cancer cells and cells of other tissue origins (breast cancer MCF-7, lung cancer H157, and colorectal cancer HCT8 cells), and we have examined whether this construct could be used for efficient expression of the suicide gene, cytosine deaminase (CD), in vivo. The PSMA promoter/enhancer expressed the luciferase reporter gene in the prostate cancer lines LNCaP and C4-2, with 8- to 20-fold higher expression than the simian virus 40 promoter/enhancer, although it was inactive in the other cell lines. This construct efficiently drove the suicide gene CD, sensitizing C4-2 cells to 5-fluorocytosine (5-FC) with the inhibitory concentration (IC(50)) <300 micromol/L in vitro. Athymic male nude mice bearing the transfected C4-2 cells were treated with intraperitoneal injections of either 5-FC (600 mg/kg) twice a day or saline solution for 3 weeks. C4-2 cell tumors were eliminated by 5-FC when they were expressing our therapeutic construct carrying CD under the regulatory control of the PSMA promoter/enhancer. Our results show the in vivo utility of the PSMA promoter/enhancer in a gene therapy situation targeting prostate cancer.
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PMID:In vivo suicide gene therapy model using a newly discovered prostate-specific membrane antigen promoter/enhancer: a potential alternative approach to androgen deprivation therapy. 1150 68

Until now, no molecular parameter has been available for predicting the metastatic potential of prostate tumours, which leaves their outcome uncertain despite an apparent benign histology or early stage. Abnormal expression of adhesion molecules, such as E-cadherin, can be contributing factors for increased invasiveness and metastatic potential. Histological analysis for E-cadherin expression was carried out on paraffin-embedded tumour tissues. Tumour metastatic potential was indirectly evaluated by detecting circulating prostate cells (CPC), using reverse transciptase-polymerase chain reaction (RT-PCR) and prostate-specific membrane antigen (PSMA) as a target. Patients were followed-up for a median of 14 months (range 10--19 months) after surgery with serum prostate-specific antigen (PSA) level measurement. Interestingly, 23 of 44 localised tumours exhibited aberrant E-cadherin expression. Prior to primary surgery, PSMA RT-PCR detected the spread of prostate cells to the blood in 24 patients. Statistical analysis showed that abnormal E-cadherin expression in the tumours was the only variable that was independently correlated with prostate cell dissemination in the blood (P<0.0001). In logistic regression analysis, abnormal E-cadherin expression was a significant independent predictor for a later biological relapse. This impaired adhesion status was clearly correlated with a haematogenous spread of the primary tumour cells. It could therefore be an objective way to restrict the indications for radical surgery to patients not presenting with this feature.
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PMID:Abnormal E-cadherin expression and prostate cell blood dissemination as markers of biological recurrence in cancer. 1150 53

The lack of a sensitive immunoassay for quantitating serum prostate-specific membrane antigen (PSMA) hinders its clinical utility as a diagnostic/prognostic biomarker. An innovative protein biochip immunoassay was used to quantitate and compare serum PSMA levels in healthy men and patients with either benign or malignant prostate disease. PSMA was captured from serum by anti-PSMA antibody bound to ProteinChip arrays, the captured PSMA detected by surface-enhanced laser desorption/ionization mass spectrometry, and quantitated by comparing the mass signal integrals to a standard curve established using purified recombinant PSMA. The average serum PSMA value for prostate cancer (623.1 ng/ml) was significantly different (P < 0.001) from that for benign prostate hyperplasia (117.1 ng/ml) and the normal groups (age <50, 272.9 ng/ml; age >50, 359.4 ng/ml). These initial results suggest that serum PSMA may be a more effective biomarker than prostate-specific antigen for differentiating benign from malignant prostate disease and warrants additional evaluation of the surface-enhanced laser desorption/ionization PSMA immunoassay to determine its diagnostic utility.
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PMID:Quantitation of serum prostate-specific membrane antigen by a novel protein biochip immunoassay discriminates benign from malignant prostate disease. 1150 47

Prostate-specific membrane antigen (PSMA) is a trans-membrane protein specifically expressed in LNCaP cells, malignant human prostate tissues, and the surrounding neovasculature. PSMA is a unique exopeptidase with reactivity toward poly-gamma-glutamated folates. It can sequentially remove the poly-gamma-glutamyl termini. To target prostate tumor cells, a novel procytolytic peptide was designed with a backbone consisting of an amoebapore H3 domain modified by two gamma-linked glutamate residues at the epsilon-amino group of the COOH-terminal lysine residue. The strategy behind the design of this prolytic peptide was to inactivate the lytic amoebapore H3 peptide by replacing its functionally important COOH-terminal positive charge with negatively charged groups, which in turn might be selectively removed by the PSMA exopeptidase. This peptide exhibited little cytolytic activity toward PSMA-negative cells, such as PC-3 cells. On the other hand, this peptide exhibited strong cytolytic activity toward PSMA-positive LNCaP cells in a concentration-dependent manner. The carboxypeptidase inhibitor 4,4'-phosphonicobis (butane-1,3-dicarboxylic acid) can inhibit this activity. Moreover, this peptide also exhibited cytolytic activity toward PSMA cDNA-transfected PC-3 cells.
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PMID:In vitro targeted killing of prostate tumor cells by a synthetic amoebapore helix 3 peptide modified with two gamma-linked glutamate residues at the COOH terminus. 1155 51

Prostate-specific membrane antigen (PSMA) is a potential target in prostate cancer patients because it is very highly expressed and because it has been reported to be upregulated by androgen deprivation. This review discusses the historical background, biochemical characteristics, gene regulation, potential for targeting, tissue localization, and a novel T-body strategy.
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PMID:A unique folate hydrolase, prostate-specific membrane antigen (PSMA): a target for immunotherapy? 1164 7

To reproduce the structural and functional differentiation of human prostatic acini in vivo, prostatic epithelial and stromal cells derived from human primary cultures were cocultured in Matrigel. In the absence of stroma and serum, epithelial spheroids composed of solid masses of stratified and cuboidal cells formed. Outer cells of the spheroid expressed cytokeratins 1, 5, 10, and 14, whereas the inner cells expressed cytokeratin 18. The addition of 2% serum induced formation of a lumen surrounded by a layer of one or two cuboidal and columnar epithelial cells. The further addition of stromal cultures, dihydrotestosterone, and estrogen induced polarization of the epithelium and increased spheroid-forming efficiency. Epithelium expressed either cytokeratin 18 alone or additionally cytokeratins 1, 5, 14, and 10. All spheroid epithelium expressed prostate-specific antigen and prostate-specific membrane antigen. Androgen receptor was only detected in the presence of stroma, serum, and hormones. Thus, development of a functional and morphologically correct prostate gland in vitro is dependent on extracellular matrix, steroid hormones, and factors from stromal cells and serum.
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PMID:Experimental prostate epithelial morphogenesis in response to stroma and three-dimensional matrigel culture. 1175 58

Artificial receptors provide a promising approach to target T lymphocytes to tumor antigens. However, the receptors described thus far produce either an activation or a co-stimulatory signal alone, thus limiting the spectrum of functions accomplished by the genetically modified cells. Here we show that human primary T lymphocytes expressing fusion receptors directed to prostate-specific membrane antigen (PSMA) and containing combined T-cell receptor-zeta (TCRzeta), and CD28 signaling elements, effectively lyse tumor cells expressing PSMA. When stimulated by cell-surface PSMA, retrovirally transduced lymphocytes undergo robust proliferation, expanding by more than 2 logs in three weeks, and produce large amounts of interleukin-2 (IL-2). Importantly, the amplified cell populations retain their antigen-specific cytolytic activity. These data demonstrate that fusion receptors containing both TCR and CD28 signaling moieties are potent molecules able to redirect and amplify human T-cell responses. These findings have important implications for adoptive immunotherapy of cancer, especially in the context of tumor cells that fail to express major histocompatibility complex antigens and co-stimulatory molecules.
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PMID:Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor. 1175 65

Glutamate carboxypeptidase II (GCPII, EC 3.4.17.21) is a membrane peptidase expressed in a number of tissues such as kidney, prostate and brain. The brain form of GCPII (also known as NAALADase) cleaves N-acetyl-aspartyl glutamate to yield free glutamate. Animal model experiments show that inhibition of GCPII prevents neuronal cell death during experimental ischaemia. GCPII thus represents an important target for the treatment of neuronal damage caused by excess glutamate. In this paper we report expression of an extracellular portion of human glutamate carboxypeptidase II (amino acids 44-750) in Drosophila Schneider's cells and its purification to homogeneity. A novel assay for hydrolytic activity of recombinant human GCPII (rhGCPII), based on fluorimetric detection of released alpha-amino groups was established, and used for its enzymological characterization. rhGCPII does not show dipeptidylpeptidase IV-like activity assigned to the native form of the enzyme previously. Using a complete set of protected dipeptides, substrate specificity of rhGCPII was elucidated. In addition to the previously described substrates, four novel compounds, Ac-Glu-Met, Ac-Asp-Met and, surprisingly, Ac-Ala-Glu and Ac-Ala-Met were identified as substrates for GCPII, and their respective kinetic constants determined. The glycosylation of rhGCPII was found indispensable for the enzymatic activity.
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PMID:Substrate specificity, inhibition and enzymological analysis of recombinant human glutamate carboxypeptidase II. 1190 94


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