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

Suicide gene therapy has potential for the treatment of prostate cancer under conditions of androgen deprivation. We show here that the combination of promoter/enhancer of prostate-specific membrane antigen (PEPM) and the Cre-loxP system is a good method to express a suicide gene, namely herpes virus thymidine kinase (TK), in prostate cancer cells. We have examined this system in a castration model in vivo, in comparison with a prostate-specific antigen promoter/enhancer system (PP). In the castrated mice, the tumor luciferase activity with the combination of the PEPM plus the Cre-loxP system was about 50 times greater than that with the control GL3 plasmid. A similar increase was observed in non-castrated mice. In contrast, the luciferase activity of the plasmid PP was decreased significantly in tumors from castrated mice as compared with tumors from non-castrated control mice. Regarding the therapeutic effect, the combination plasmid PEPM-Cre plus CMV-loxP-TK exhibited a strong inhibitory effect on tumor growth in the castrated mice, as in the non-castrated mice. In contrast, PP-TK plasmid did not show any significant growth inhibition in the castrated mice. These findings indicate that the combination of PEPM and Cre-loxP system may have a good treatment effect under androgen ablation conditions in vivo, and our system may therefore be applicable to patients who have previously received androgen deprivation therapy.
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PMID:Treatment efficiency of a suicide gene therapy using prostate-specific membrane antigen promoter/enhancer in a castrated mouse model of prostate cancer. 1507 97

ProstaScint (CYT-356 or capromab pendetide, Cytogen) is an 111In-labeled monoclonal mouse antibody specific for prostate-specific membrane antigen, a prostate transmembrane glycoprotein that is upregulated in prostate adenocarcinoma. ProstaScint scans are US Food and Drug Administration approved for pretreatment evaluation of metastatic disease in high-risk patients. They are also approved for post-prostatectomy assessment of recurrent disease in patients with a rising prostate-specific antigen level. This review explores the literature on ProstaScint and its use in guiding the treatment of prostate cancer. A novel technique for identifying areas of cancer within the prostate using ProstaScint images fused with pelvic computed tomography scans is also described. The identification of areas of high antibody signal provides targets for radiotherapeutic dose escalation, with the overall goals of improving treatment outcome while preserving adjacent tissue structures and decreasing treatment morbidity.
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PMID:Role of ProstaScint for brachytherapy in localized prostate adenocarcinoma. 1522 91

Prostate-specific antigen (PSA) has long been criticized for its lack of specificity in screening for the occurrence of prostate cancer. In this study, we tried to measure levels of another biomarker, prostate-specific membrane antigen (PSM), in the peripheral circulation from subjects with either prostate cancer or benign prostatic hyperplasia (BPH). Total RNA was extracted from blood samples of 70 patients with prostate cancer and 19 with BPH. Reverse transcription was performed to convert mRNA to cDNA. The cDNA was analyzed with a novel real-time quantitative polymerase chain reaction (PCR) protocol to measure PSM mRNA levels in the circulation. Melting curve analysis was adapted to assure that correct amplification data were obtained. Results showed that 41 of 70 prostate cancer patients had positive results, whereas 9 of 19 BPH cases were negative. Therefore, the sensitivity and specificity were determined to be 58.6% and 47.4%, respectively. For comparison, traditional nested PCR was performed to investigate whether the new method was superior. The sensitivity and specificity of nested PCR were determined to be 27.1% and 57.9%, respectively. The detection limits of these two methods were 0.0005 ng (for the real-time quantitative PCR method) and 0.5 ng of PSM-cDNA (for the nested PCR method). In conclusion, we have successfully developed a novel, noninvasive real-time quantitative PCR method to detect the PSM mRNA levels in the peripheral circulation of prostate cancer subjects. This method may provide references for urologists diagnosing prostate cancer or monitoring the patient's condition after treatment.
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PMID:The use of real-time quantitative PCR to detect circulating prostate-specific membrane antigen mRNA in patients with prostate carcinoma. 1525 56

Radical prostatectomy should ideally be curative for all patients with clinically localized prostate cancer (PrCa), yet a sizeable proportion of them eventually relapse. We examined in this setting the feasibility of pre-operative risk stratification for early post-operative relapse using reverse transcriptase polymerase chain reaction (RT-PCR) for prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) transcripts in preoperative bone marrow (BM) biopsies and peripheral blood (PBL) samples. Nested RT-PCR for PSA and PSMA transcripts were performed in RNA from BM biopsies and PBL samples prospectively obtained from 111 men newly diagnosed, by trans-rectal ultrasound (TRUS)-guided biopsy, with clinically localized PrCa and scheduled to undergo radical prostatectomy, according to their respective doctors' recommendation. Molecular analysis for each sample (PBL or BM) was considered positive only if both PSA and PSMA transcripts were detectable. Serial serum PSA level measurements served for biochemical follow-up and detection of biochemical failure (PSA >0.2 ng/ml). PBL and BM RT-PCR molecular staging delineated three groups of patients (a) PBL-BM- (72 patients, 65%), (b) PBL+BM+ (29 patients, 26%), and (c) PBL+BM- (10 patients, 9%). These three groups corresponded to low, high, and intermediate risk for early post-prostatectomy recurrence (median time to biochemical failure of >38, 8, and >28 months, respectively). Multivariate analysis confirmed that molecular staging status was independent predictor of disease-free survival, after adjusting for PSA levels and Gleason score. In clinically localized PrCa, combined PSA/PSMA RT-PCR in PBL and BM is an independent predictor of time to biochemical failure following radical prostatectomy.
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PMID:Molecular staging by RT-pCR analysis for PSA and PSMA in peripheral blood and bone marrow samples is an independent predictor of time to biochemical failure following radical prostatectomy for clinically localized prostate cancer. 1567 47

PSES is a chimeric enhancer containing enhancer elements from prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) genes that are prevalently expressed in androgen-independent prostate cancers. PSES shows strong activity equivalent to cytomegalovirus (CMV) promoter, specifically in PSA/PSMA-positive prostate cancer cells, the major cell types in prostate cancer in the absence of androgen. We developed a recombinant adenovirus (AdE4PSESE1a) by placing adenoviral E1a and E4 genes under the control of the bidirectional enhancer PSES and enhanced green fluorescent protein gene for the purpose of intratumoral virus tracking under the control of CMV promoter. Because of PSES being very weak in nonprostatic cells, including HEK293 and HER911 that are frequently used to produce recombinant adenovirus, AdE4PSESE1a can only be produced in the HER911E4 cell line which expresses both E1 and E4 genes. AdE4PSESE1a showed similar viral replication and tumor cell killing activities to wild-type adenovirus in PSA/PSMA-positive prostate cancer cells. The viral replication and tumor cell killing activities were dramatically attenuated in PSA/PSMA-negative cells. To test whether AdE4PSESE1a could be used to target prostate tumors in vivo, CWR22rv s.c. tumors were induced in nude mice and treated with AdE4PSESE1a via intratumoral and tail vein injection. Compared to tumors treated with control virus, the growth of CWR22rv tumors was dramatically inhibited by AdE4PSESE1a via tail vein injection or intratumoral injection. These data show that adenoviral replication can be tightly controlled in a novel fashion by controlling adenoviral E1a and E4 genes simultaneously with a single enhancer.
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PMID:Gene therapy for prostate cancer by controlling adenovirus E1a and E4 gene expression with PSES enhancer. 1575 94

The loss of immunogenic epitopes by tumors has urged the development of vaccines against multiple epitopes. Recombinant DNA technologies have opened the possibility to develop multiepitope vaccines in a relatively rapid and efficient way. In this study, several DNA fragments encoding multiple cytotoxic T lymphocyte (CTL) and T helper (Th) cell epitopes were selected from human prostate-specific membrane antigen (hPSM), mouse prostatic acid phosphatase (mPAP), and human prostate-specific antigen (hPSA), These DNA fragments were ligated together to form a novel fusion gene, termed 3P gene. The 3P gene and human IgG Fc gene were inserted into pcDNA3.1 to construct a DNA vaccine designated psig-3P-Fc. Vaccination with psig-3P-Fc by gene gun inoculation induced strong antitumor response in a mouse tumor model, which significantly inhibited tumor growth and prolonged survival time of the tumor-bearing mice. In vitro, when lymphocytes were stimulated by psig-3P-Fc-transfected autologous peripheral blood mononuclear cells (PBMC), CTLs were induced which could specifically kill hPSM-, hPAP-, or hPSA-expressing tumor cells. These observations provide a new vaccine strategy for cancer therapy through concomitant enhancement of antigen specific CD4(+) helper and CD8(+) cytotoxic T-cell responses against tumors.
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PMID:Specific antitumor immune response induced by a novel DNA vaccine composed of multiple CTL and T helper cell epitopes of prostate cancer associated antigens. 1589 16

The development of targeted therapies for prostate cancer has exploited various elements of prostate biology. The androgen-dependence of prostate cancer continues to be the focus for the development of new drugs and the analysis of details of the intermolecular interactions of the androgen receptor. Importantly, new applications of androgen ablation therapy have proven to have the greatest effect on cause-specific and overall survival during the last decade. Prostate epithelial cells express a number of tissue-specific proteins that have been the target either for antibody-directed therapies, in the case of prostate-specific membrane antigen, or target-activated therapies in the case of prostate-specific antigen, a serine protease. Prostate-specific proteins have also been targeted by the development of vaccines that have entered clinical trials. Humanized monoclonal antibodies and small molecules designed to inhibit oncogenic signalling pathways have been subjected to clinical trials in prostate cancer with limited success. The application of pathway inhibitors to prostate cancer therapy has been limited because no common dominant oncogenic mutation affecting signal kinase activation in prostate cancer has yet been identified. The interaction of signal kinase inhibitors with androgen ablation and with cytotoxic chemotherapy remains to be explored.
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PMID:Targeted therapies for prostate cancer. 1593 16

Our aim is the identification and correlation of changes in tumor-associated protein expression which results from therapy. LNCaP tumors, excised from nude mice treated either by orchiectomy or with the chemotherapeutic agent paclitaxel, were evaluated for the expression of proteins and receptors associated with growth, differentiation, and angiogenesis using immunohistologic procedures. Compared to untreated control tumors, both treatments reduced the expression of vascular endothelial growth factor (VEGF), prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA), androgen receptor (AR), and epidermal growth factor receptor (EGFR). The effect of paclitaxel treatment on AR expression was the most significant (P = .005). Of particular interest was identifying a significant correlation (P < .000801) between PSMA and VEGF expression regardless of treatment modality. These altered expressions suggest that PSMA may also be a marker for angiogenesis and could represent a target for deliverable agents recognizing either prostatic tumors or endothelial development. Cell surface PSMA would then present a unique target for treatment of patients early in their development of prostatic metastases.
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PMID:Correlation between PSMA and VEGF expression as markers for LNCaP tumor angiogenesis. 1619 87

Androgen is a major growth factor in the normal prostate and determines the overall number of prostate cells. Metastatic prostate cancer, while initially responsive to androgen ablation, eventually becomes hormone-refractory and resistant to many treatments. Unfortunately, there are very few agents in the preclinical stage with a seemingly promising future for hormone-refractory prostate cancer (HRPC) that are actually taken through the complete drug development process, including US Food and Drug Administration approval. Many novel strategies under investigation for treating HRPC target metastatic prostate cancer cells that are neither androgen-dependent nor in the proliferative state. Examples of therapies that target this so-called "Achilles' heel" of HRPC include immune therapy, gene therapy, angiogenesis inhibition, and activation of programmed cell death. Unique properties of HRPC allow for the development of novel treatments that target prostate-specific antigen (PSA), human glandular kallikrein-2, or prostate-specific membrane antigen. An inactive prodrug with a thapsigargin analogue, a sesquiterpene lactone from the plant Thapsia garganica, is currently under investigation specifically for the targeted therapy of HRPC. Preclinical data suggest the PSA-targeting abilities of this novel therapy are associated with a nearly complete cessation of tumour growth with minimal toxicity.
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PMID:New strategies for the medical treatment of prostate cancer. 1635 37

DNA vaccines provide an attractive technology against cancer because of their safety record in humans and ease of construction, testing and manufacture. In this study, several DNA fragments encoding multiple cytotoxic T lymphocyte (CTL) and T helper cell epitopes were selected from human prostate-specific membrane antigen (hPSM), mouse prostatic acid phosphatase (mPAP), and human prostate-specific antigen (hPSA). These DNA fragments were ligated together to form a novel fusion gene, termed the 3P gene. The secondary lymphoid tissue chemokine (SLC), 3P and human immunoglobulin G Fc genes were inserted into pcDNA3.1 to construct a DNA vaccine, designated pSLC-3P-Fc. After vaccination, the DNA is taken up by cells that produce and secrete the SLC-3P-Fc fusion proteins, termed chemotactic antigen (chemo-antigen). The secreted chemo-antigens, in addition to promoting the co-localization of naive, non-polarized memory T cells and dendritic cells, are efficiently captured and processed by dendritic cells via receptor-mediated endocytosis and then cross-presented to both major histocompatibility complex class I and class II in a cognate manner. The results of this study demonstrate that vaccination with pSLC-3P-Fc by gene gun inoculation induced a strong antitumour response in a mouse tumour model, which significantly inhibited tumour growth and prolonged the survival time of the tumour-bearing mice. In vitro, the secreted SLC-3P-Fc fusion protein can attract lymphocytes from human peripheral blood mononuclear cells (PBMC); when human lymphocytes were stimulated by pSLC-3P-Fc-transfected autologous PBMC, CTLs were induced which could specifically kill hPSM-, hPAP-, or hPSA-expressing tumour cells. These observations provide a new vaccine strategy for cancer therapy through promoting the co-localization of lymphocytes and the concomitant enhancement of antigen-specific CD4+ helper and CD8+ cytotoxic T-cell responses against tumour.
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PMID:Enhancement of antitumour immunity by a novel chemotactic antigen DNA vaccine encoding chemokines and multiepitopes of prostate-tumour-associated antigens. 1647 62


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