Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.17.21 (prostate-specific membrane antigen)
 1,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostate cancer represents an ideal target for radioimmunotherapy based on the pattern of spread, including bone marrow and lymph nodes, sites that typically receive high levels of circulating antibody, and the small volume of disease, ideally suited for antibody delivery and antigen access. This review explores possible antibody targets in prostate cancer and focuses on the potential role for radioimmunotherapy by highlighting several clinical trials involving radiolabeled anti-prostate-specific membrane antigen monoclonal antibody J591. Prostate-specific membrane antigen, a highly prostate-restricted transmembrane glycoprotein with increased expression in high-grade, metastatic, and hormone-refractory disease, represents an ideal target for monoclonal antibody therapy in prostate cancer. Radiolabeled anti-prostate-specific membrane antigen monoclonal antibody J591 trials using the radiometals yttrium-90 and lutetium-177 have demonstrated manageable myelotoxicity, no significant nonhematologic toxicity, excellent targeting of soft-tissue and bone metastases, and preliminary efficacy including prostate-specific antigen and measurable disease responses. Additional studies are under way to better define the activity of radiolabeled antibody therapy as well as the role for fractionated therapy and combination approaches with taxane-based chemotherapy.
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PMID:Clinical utility of radiolabeled monoclonal antibodies in prostate cancer. 1672 7

Composite promoters combining the prostate-specific antigen (PSA) enhancer core element with promoter elements derived from gene coding for human prostate-specific transglutaminase gene, prostate-specific membrane antigen gene, prostate-specific antigen, rat probasin or phosphoglycerate kinase were characterized for their ability to specifically express the enhanced green fluorescent protein (EGFP) gene in prostate versus non-prostate cancer cell lines when transferred with a human immunodeficiency virus-1-based lentiviral vector. By themselves minimal proximal promoter elements were found to inefficiently promote relevant tissue-specific expression; in all the vectors tested, addition of the PSA enhancer core element markedly improved EGFP expression in LnCaP, a cancer prostate cell line used as a model for prostate cancer. The composite promoter was inactive in HuH7, a hepatocarcinoma cell line used as a model of neighboring non-prostate cancer cells. Among the promoters tested, the combination of the PSA enhancer and the rat probasin promoter showed both high specificity and a strong EGFP expression. Neither a high viral input nor the presence of the cPPT/CTS sequence affected composite promoter behavior. Our data suggest that composite prostate-specific promoters constructed by combining key elements from various promoters can improve and/or confer tissue specific expression in a lentiviral vector context.
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PMID:Use of the PSA enhancer core element to modulate the expression of prostate- and non-prostate-specific basal promoters in a lentiviral vector context. 1674 21

The recombinant prostate-specific PPT sequence comprises a prostate-specific antigen enhancer, a PSMA enhancer and a TARP promoter. It is transcriptionally active in human prostate cancer cells both in the presence and absence of testosterone. However, in experimental murine prostate cancer, it has no detectable transcriptional activity. Herein, we describe that the PPT sequence in combination with a two-step transcriptional amplification (TSTA) system becomes active also in murine prostate cancer cells. An adenovirus with TSTA-amplified PPT-controlled expression of the luciferase reporter gene, Ad[PPT/TSTA-Luc], has up to 100-fold higher prostate-specific transcriptional activity than a non-amplified PPT-based adenovirus, Ad[PPT-Luc], in human cells. In addition, Ad[PPT/TSTA-Luc] confers prostate-specific transgene expression in murine cells, with an activity that is approximately 23% of Ad[CMV-Luc] in the transgenic adenocarcinoma of the mouse prostate (TRAMP)-C2 cells. Moreover, to visualize luciferase expression in living mice a charge-coupled device camera was used. Ad[PPT/TSTA-Luc] yielded approximately 30-fold higher transgene expression than Ad[PPT-Luc] in LNCaP tumor xenografts. Importantly, Ad[PPT/TSTA-Luc] also showed activity in murine TRAMP-C2 tumors, whereas Ad[PPT-Luc] activity was undetectable. These results highlight that the recombinant PPT sequence is active in murine prostate cancer cells when augmented by a TSTA system. This finding opens up for preclinical studies with prostate-specific therapeutic gene expression in immunocompetent mice.
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PMID:Two-step amplification of the human PPT sequence provides specific gene expression in an immunocompetent murine prostate cancer model. 1705 14

We previously reported that several DNA fragments from human prostate-specific membrane antigen (hPSM), mouse prostatic acid phosphatase (mPAP), and human prostate-specific antigen (hPSA) genes were selected and fused to create a novel hPSM-mPAP-hPSA fusion gene (named 3P gene), and human secondary lymphoid tissue chemokine (SLC), 3P, and human IgG Fc genes were inserted into pcDNA3.1 to construct a DNA vaccine, designated pSLC-3P-Fc. In this report, to establish a more efficient treatment for immunotherapy against prostate cancer, the construct was transfected into B16F10 to generate gene-modified tumor cell vaccine (named B16F10-SLC-3P-Fc). In poorly immunogenic B16F10 mouse melanoma model, the immunization with B16F10-SLC-3P-Fc resulted in a strong antitumor response and 50% of tumor-bearing mice achieved long-term survival (>120 days). In vivo depletion of lymphocytes indicated that CD8(+) T cells were involved in the direct tumor killing, whereas CD4(+) T lymphocytes were required for the induction of CD8(+) CTL response in B16F10-SLC-3P-Fc-immunized mice. Splenocytes from B16F10-SLC-3P-Fc-immunized mice specifically recognized and lysed PSM, PAP, PSA, and 3P expressing tumor cells. The combined therapy of B16F10-SLC-3P-Fc plus anti-B7-H1 MAbs further enhanced the immune response. Rechallenge experiment showed that a persistent memory response was successfully induced by the combined therapy. These observations suggest pSLC-3P-Fc-modified tumor cells could serve as a vaccine against prostate cancer, and the therapy combined with anti-B7-H1 MAbs further enhanced the antitumor immune response.
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PMID:Potent systemic antitumor immunity induced by vaccination with chemotactic-prostate tumor associated antigen gene-modified tumor cell and blockade of B7-H1. 1718 Apr 70

Distinguishing aggressive prostate cancer from indolent disease represents an important clinical challenge, because current therapy may lead to overtreatment of men with limited disease. The prostate-specific membrane antigen (PSMA) is a membrane-bound glycoprotein that is highly restricted to the prostate. Previously, studies analyzing the expression of PSMA have found an up-regulation in correlation with prostate cancer, particularly in advanced cancer. This association is ideal for an application as a prognostic marker. In the current study, we characterized PSMA expression in a high-risk cohort and evaluated its potential use as predictive marker of prostate-specific antigen (PSA) recurrence. PSMA expression was analyzed by immunohistochemistry using tissue microarrays composed of tumor samples from 450 patients. Protein intensity was recorded using a semiautomated quantitative microscope system (ACIS II; Clarient Chromavision Medical Systems, San Juan Capistrano, CA). PSMA expression levels differed significantly (P < .001) between benign prostatic tissue, localized prostate cancer, and lymph node metastases. Dividing the cohort into high- and low-PSMA expressing cancers based on the median area of positive staining, we found that high PSMA levels were associated with significant increase of PSA recurrence (P = .004). This was independent of clinical parameters such as lymph node tumor burden (lymph node density, >20%; P < .001), extraprostatic extension (P = .017), seminal vesicle invasion (P < .001), and high Gleason score (8-10, P = .006). In a multivariate model, PSMA expression and metastases to pelvic lymph nodes were significantly associated with time to PSA recurrence (HR, 1.4; 95% confidence interval, 1.1-2.8, P = .017; and hazard ratio, 5; 95% confidence interval, 2.6-9.7, P < .001, respectively). In summary, PSMA is independently associated with PSA recurrence in a high-risk cohort and thus might provide insight into the additional use of adjuvant therapy. Validation on other cohorts is required.
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PMID:Prostate-specific membrane antigen expression as a predictor of prostate cancer progression. 1732 Jan 51

Prostate cancer is a major cause of mortality in men in the Western world. Although treatment of early stage prostate cancer with radiation therapy or prostatectomy is efficient in most cases, some patients develop a fatal hormone-refractory disease. Treatments in this case are limited to aggressive chemotherapies, which can reduce serum prostate-specific antigen (PSA) levels in some patients. Taxane- and platinum-compound-based chemotherapies produce a survival benefit of only a few months. Therefore, it is crucial to develop novel, well tolerated treatment strategies. Over the past years, immunotherapy of hormone-refractory prostate cancer has been studied in numerous clinical trials. The fact that the prostate is a non-essential organ makes prostate cancer an excellent target for immunotherapy. Administration of antibodies targeting the human epidermal growth factor receptor-2 or the prostate-specific membrane antigen led to stabilisation of PSA levels in several patients. Vaccination of prostate cancer patients with irradiated allogeneic prostate cell lines has demonstrated that whole cell-based vaccines can significantly attenuate increases in PSA. Two different recombinant viral expression vectors have been applied in prostate cancer treatment: poxvirus and adenovirus vectors. Both vaccines have the advantages of using a natural method to induce immune responses and achieving high levels of transgene expression. Vaccinia viruses in combination with recombinant fowlpox or canarypox virus have been used to express recombinant PSA. Several studies demonstrated that this approach is safe and can lead to stabilisation of PSA values. A very promising approach in prostate cancer immunotherapy is vaccination of patients with dendritic cells. Thereby, peptides, recombinant proteins, tumour lysates or messenger RNA have been used to deliver antigens to autologous dendritic cells. Loading of dendritic cells with up to five different peptides derived from multiple proteins expressed in prostate cancer demonstrated that cytotoxic T-cell responses could be elicited in prostate cancer patients. Sipuleucel-T (APC8015), an immunotherapy product consisting of antigen-presenting cells, loaded ex vivo with a recombinant fusion protein consisting of prostatic acid phosphatase linked to granulocyte-macrophage colony-stimulating factor, demonstrated in a phase III, placebo-controlled trial an improvement in median time to disease progression. The improvement in overall survival was 4.5 months for sipuleucel-T-treated patients compared with the placebo group. Although there is a minor increase in overall survival of metastatic prostate cancer patients with some approaches, more effective therapeutic strategies need to be developed.
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PMID:Advances in prostate cancer immunotherapies. 1736 49

There has been a resurgence of interest in developing noncytotoxic immune therapies for patients with either hormone-naive biochemically relapsed post-primary therapy or castrate metastatic prostate cancer. The rationale for developing an immunotherapeutic approach has been based on the overexpression and underglycosylation of a wide variety of altered "self" molecules including prostate-specific antigen (PSA), acid phosphatase (ACP), prostate stem cell antigen (PSCA), and prostate-specific membrane antigen (PSMA), which can serve as targets for immune recognition and attack. In addition, such a strategy could theoretically make use of the patient's immune system to fight the tumor particularly if their disease is of reasonably low volume. A variety of immunotherapeutic approaches have been explored through phase I, II, and now phase III trials demonstrating that immunologic tolerance could be broken, as evidenced by the development of hightiter antibodies and T-cell responses specific for the tumor. What appears to be revolutionizing the immunotherapy field is the combination of vaccines with cytokines or immune modulators, which not only potentiate immune reactivity in vivo but foster dramatic antitumor responses. This review explores the challenges now faced in establishing a role for immune therapies for prostate cancer treatment.
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PMID:Emerging role of immunotherapy in the management of prostate cancer. 1744 37

The histologic distinction between high-grade prostate cancer and infiltrating high-grade urothelial cancer may be difficult, and has significant implications because each disease may be treated very differently (ie, hormone therapy for prostate cancer and chemotherapy for urothelial cancer). Immunohistochemistry of novel and established prostatic and urothelial markers using tissue microarrays (TMAs) were studied. Prostatic markers studied included: prostate-specific antigen (PSA), prostein (P501s), prostate-specific membrane antigen (PSMA), NKX3.1 (an androgen-related tumor suppressor gene), and proPSA (pPSA) (precursor form of PSA). "Urothelial markers" included high molecular weight cytokeratin (HMWCK), p63, thrombomodulin, and S100P (placental S100). TMAs contained 38 poorly differentiated prostate cancers [Gleason score 8 (n=2), Gleason score 9 (n=18), Gleason score 10 (n=18)] and 35 high-grade invasive urothelial carcinomas from radical prostatectomy and cystectomy specimens, respectively. Each case had 2 to 8 tissue spots (0.6-mm diameter). If all spots for a case showed negative staining, the case was called negative. The sensitivities for labeling prostate cancers were PSA (97.4%), P501S (100%), PSMA (92.1%), NKX3.1 (94.7%), and pPSA (94.7%). Because of PSA's high sensitivity on the TMA, we chose 41 additional poorly differentiated primary (N=36) and metastatic (N=5) prostate carcinomas which showed variable PSA staining at the time of diagnosis and performed immunohistochemistry on routine tissue sections. Compared to PSA, which on average showed 18.8% of cells with moderate to strong positivity, cases stained for P501S, PSMA, and NKX3.1 had on average 42.5%, 53.7%, 52.9% immunoreactivity, respectively. All prostatic markers showed excellent specificity. HMWCK, p63, thrombomodulin, and S100P showed lower sensitivities in labeling high-grade invasive urothelial cancer in the TMAs with 91.4%, 82.9%, 68.6%, and 71.4% staining, respectively. These urothelial markers were relatively specific with only a few prostate cancers showing scattered (<or=2%) weak-moderate positive cells. In summary, PSA can be used as the first screening marker for differentiating high-grade prostate adenocarcinoma from high-grade urothelial carcinoma. Immunohistochemistry for P501S, PSMA, NKX3.1, and pPSA are useful when high-grade prostate cancer is suspected based on the morphology or clinical findings, yet shows negative or equivocal PSA staining. HMWCK and p63 are superior to the novel markers thrombomodulin and S100P.
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PMID:Immunohistochemical differentiation of high-grade prostate carcinoma from urothelial carcinoma. 1766 50

The introduction of prostate-specific antigen (PSA) revolutionized prostate cancer (PCa) screening and ushered the PSA era. However, its use as a screening tool remains controversial and changes in the epidemiology of PCa have strongly limited its prognostic role. Therefore, we need novel approaches to improve our ability to detect PCa and foretell the course of the disease. To improve the specificity of total PSA, several approaches based on PSA derivatives have been investigated such as age-specific values, PSA density (PSAD), PSAD of the transition zone, PSA velocity and assessment of various isoforms of PSA. With recent advances in biotechnology such as high-throughput molecular analyses, many potential blood biomarkers have been identified and are currently under investigation. Given the plethora of candidate PCa biomarkers, we have chosen to discuss a select group of candidate blood-based biomarkers including human glandular kallikrein, early prostate cancer antigens, insulin-like growth factor-I (IGF-I) and its binding proteins (IGFBP-2 and IGFBP-3), urokinase plasminogen activation system, transforming growth factor-beta1, interleukin-6, chromogranin A, prostate secretory protein, prostate-specific membrane antigen, PCa-specific autoantibodies and alpha-methylacyl-CoA racemase. While these and other markers have shown promise in early phase studies, no single biomarker is likely to have the appropriate degree of certainty to dictate treatment decisions. Consequently, the future of cancer prognosis may rely on small panels of markers that can accurately predict PCa presence, stage, metastasis, and serve as prognosticators, targets and/or surrogate end points of disease progression and response to therapy.
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PMID:New circulating biomarkers for prostate cancer. 1799 18

Small cell carcinoma of prostate is rare, with the literature consisting of case reports and small series. The current work analyzes the morphology and immunohistochemistry of 95 cases of prostatic small cell carcinoma diagnosed at our institution. Specimens included 55 needle biopsies, 27 transurethral resections, 4 radical prostatectomies, and 9 biopsies from metastatic sites (some patients with >1 procedure). Patients ranged in age from 44 to 92 years old (mean: 69 y). Although serum prostate-specific antigen (PSA) in some cases was very high (up to 1896 ng/mL), the median value was only 4.0 ng/mL. Of cases with available information, 33/78 (42%) had a history of usual prostatic adenocarcinoma. The interval between the diagnosis of small cell carcinoma and prior usual prostatic cancer ranged from 1 to 300 months (median 25 mo). Pure small cell carcinoma was seen in 54/95 (57%) of cases with the remaining cases admixed with prostate adenocarcinoma. In cases with adenocarcinoma, there was a sharp demarcation between small cell carcinoma and adenocarcinoma in 20.5% of cases; in the remaining cases there was gradual merging of the 2 components. In mixed cases, small cell carcinoma predominated (median: 80% of the tumor); the Gleason score of the adenocarcinoma was > or =8 in 85% of these cases. In 61 cases (64%), small cell carcinoma was classic "oat cell" morphology with remaining the "intermediate cell" variant. Of the 95 cases: necrosis was seen in 40% (2% to 95% of the tumor); giant bizarre cells in 19%; Indian filing in 21%; rosette formation in 29%; focal vacuolated cytoplasm in 18%; and desmoplasia in 20%. Most (88%) of small cell carcinoma were positive for at least 1 neuroendocrine marker. In the small cell carcinoma component, 14/73 (19%) were positive for PSA, 17/61 (28%) positive for prostein (P501S), and 15/59 (25%) positive for prostate-specific membrane antigen, although often very focally. Stains for thyroid transcription factor-1 were positive in 23/44 (52.3%) cases. In this, the largest study of prostatic small cell carcinoma, we highlight the presence of morphologic features that may result in its underdiagnosis. Other more classic histologic features of small cell carcinoma along with rosettes are critical for its accurate diagnosis. P501S and prostate-specific membrane antigen were better in identifying the prostatic origin of small cell carcinoma than PSA, although the majority (60%) of prostatic small cell carcinomas were negative for all 3 markers.
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PMID:Small cell carcinoma of the prostate. A morphologic and immunohistochemical study of 95 cases. 1816 72


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