Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Understanding of molecular genetic mechanisms underlying prostate carcinogenesis would be greatly advanced by in vitro models of prostate tumors representing primary tumors. We have successfully established a neoplastic immortalized human prostate epithelial (HPE) clonal culture derived from a primary tumor of a prostate cancer patient (RC-58T) with hTERT, the catalytic subunit of telomerase. The early passage RC-58T cells derived from a radical prostatectomy specimen of a 52-year-old white male patient was transduced through infection with a retrovirus vector expressing the hTERT for the establishment of the RC-58T/hTERT cell line. One clonal line, soft-agar derived from the RC-58T/hTERT cell line, was isolated and further characterized phenotypically and genetically. These clonal (RC-58T/hTERT SA#4) cells are currently growing well at passage 70 and exhibit transformed morphology. The RC-58T/hTERT SA#4 line expressed a high level of telomerase activity and showed anchorage-independent growth in soft agar. The clonal line like the untransduced RC-58T cells (passage 3) expressed prostate specific antigen (PSA), androgen receptor (AR), prostate stem cell antigen (PSCA), and an androgen-regulated prostate specific gene NKX3.1, P16, and cytokeratin (CK) 8. Growth is slightly stimulated by dihydrotestosterone (DHT), and lyates are immunoreactive with AR antibody by Western blot analysis. More importantly, this clonal line produced adenocarcinomas when transplanted into SCID mice. A number of chromosome alterations were observed including the loss of chromosome Y, 1q, 2p, 3p, 4q, 8p, 11p, 14p, 17p and 18q. Our results demonstrate that this primary tumor-derived HPE cell line retained its neoplastic phenotypes and its prostate specific markers and should allow elucidating molecular and genetic alterations involved in prostate cancer. This is the first documented case of an AR and PSA expressing telomerase established human prostate cancer cell line with neoplastic phenotypes from a primary tumor of a prostate cancer patient.
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PMID:A telomerase-immortalized primary human prostate cancer clonal cell line with neoplastic phenotypes. 1537 56

The generation of suitable in vitro models is critical for understanding the process associated with the development and progression of prostate cancer in high-risk African-American men. However, the generation of long-term human prostate epithelial cell lines derived from primary human prostate epithelium have been unsuccessful due to the absence of in vitro immortalization. We have successfully established an immortal human prostate epithelial cell line from primary benign tissues of African-American prostate cancer patients by using telomerase. The actively proliferating secondary African-American prostate epithelial RC-165N cells, derived from benign prostate tissue of a radical prostatectomy specimen, were transduced through infection with a retrovirus vector expressing the human telomerase catalytic subunit (hTERT). A high level of telomerase activity was detected in RC-165N/hTERT cells but not in RC-165N cells. RC-165N/hTERT cells are currently growing well at passage 50 whereas RC-165N cells senesced within passage 3. RC-165N/hTERT cells exhibit epithelial morphology. These immortalized cells showed no cell growth in soft agar, and no tumor formation in SCID mice. The RC-165N/hTERT cells express androgen-regulated prostate-specific homobox gene. NKX 3.1 and epithelial cell specific cytokeratin 8, androgen receptor (AR), prostate stem cell antigen and p16, but not PSA. AR protein was detected by Western blot analysis.
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PMID:Androgen and androgen receptor antagonist responsive primary African-American benign prostate epithelial cell line. 1581 12

Prostate stem cell antigen (PSCA), a homologue of the Ly-6/Thy-1 family of cell surface antigen, is expressed by a majority of human prostate cancers and is a promising target for prostate cancer immunotherapy. To obtain the specific peptide binding with PSCA for targeted immunotherapy, PSCA gene was obtained by RT-PCR from human prostate cancer cell line DU145 and the transcated PSCA (tPSCA) gene was cloned into vector pQE30 for soluble expression in E. coli. The identity of recombinant tPSCA was confirmed through ELISA and western blot by use of anti-PSCA monoclonal antibody. Then the 12-peptide phage display library was screened with the purified tPSCA protein for its specific binding peptide through 3 rounds panning. For identifying the peptide's specificity, the peptide was coupled with EGFP (enhanced green fluorecent protein) by recombinant DNA technology and the recombinant coupled protein was termed 11-EGFP. The binding specificity with tPSCA of 11-EGFP was further confirmed by ELISA and competitive inhibition experiment. Flow cytometry demonstrated its binding specificity with cell line DU145. In conclusion, a 12-amino-acid peptide which could bind with PSCA specifically was found and it may be a potential tool for targeted immunotherapy of prostate carcinoma.
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PMID:[Expression of prostate stem cell antigen (PSCA) and selection of its specific binding peptide]. 1597 92

Activation of immune defense mechanisms against tumor antigens appears to be a promising therapeutic option for advanced prostate cancer (PCa). Specific immunotherapy critically depends on target antigens that are selectively expressed in the tumorous and optional in the normal prostate tissue in sufficient amounts. Although several prostate antigens have been described and some have already been used in clinical trials, a detailed comparative evaluation of their tissue-specificity and expression levels is still lacking. We determined the transcript levels of eight prostate targets (PSA, PAP, PSCA, PSGR, Prostein, PSMA, AIbZIP, trp-p8) in 16 different tissues by quantitative PCR and calculated a tissue-specificity index (TSI) for each molecule. Besides a preferential expression in prostate for all targets, striking differences in the expression levels and TSI were revealed which may be important for the selection of appropriate antigens for immunotherapy of PCa.
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PMID:Tissue-specificity of prostate specific antigens: comparative analysis of transcript levels in prostate and non-prostatic tissues. 1604 56

Prostate stem cell antigen (PSCA), a 123-amino acid cell surface glycoprotein, is highly expressed in both local and metastatic prostate cancers as well as in a large proportion of bladder and pancreatic cancers. PSCA overexpression correlates with a high risk of recurrence after primary therapy for prostate cancer. We have reported previously that anti-PSCA monoclonal antibody (mAb) 1G8 inhibits tumor growth, prevents metastasis, and prolongs the survival of mice inoculated with human prostate cancer cell lines and xenografts. The current study was undertaken to elucidate the mechanism of action of anti-PSCA antibody therapy. In particular, we asked whether antitumor activity resulted from recruitment of an immune response or a direct effect on the tumor cell itself. In vitro assays show that both intact 1G8 and F(ab')2 fragments of 1G8 induce prostate cancer cell death. The anti-PSCA antibody-induced cell death is caspase independent and requires antigen cross-linking. These results were confirmed in in vivo models in which both 1G8 and F(ab')2 fragments were able to inhibit prostate tumor formation and growth equally. These results suggest that the anti-PSCA mAb 1G8 acts by a direct, Fc-independent mechanism to inhibit prostate tumor growth both in vitro and in vivo.
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PMID:Anti-prostate stem cell antigen monoclonal antibody 1G8 induces cell death in vitro and inhibits tumor growth in vivo via a Fc-independent mechanism. 1623 Apr 14

We have used gene expression profiling to characterize genes regulated by the anti-tumor non-steroidal anti-inflammatory drug (NSAID)-like agent R-flurbiprofen (RFB) in murine TRAMP prostate cancer. Mice with spontaneous, palpable tumors were treated with RFB 25 mg/(kgd) x 7d orally, or vehicle only. RNA was then extracted from tumor tissue and used for microarray analysis with Affymetrix chips. Fifty-eight genes were reproducibly regulated by RFB treatment. One of the most highly up-regulated genes was prostate stem cell antigen (psca). We used TRAMP C1 murine prostate cancer cells to examine potential mechanisms through which RFB could regulate psca. RFB induced dose-dependent expression of PSCA protein, and activity of the psca promoter, in TRAMP C1 cells in culture. Increased psca promoter activity was also seen following treatment of cells with sulindac sulfone, another NSAID-like agent, but not with celecoxib treatment. RFB activation of the psca promoter could be attenuated by co-transfection of dominant-negative akt and h-ras constructs, but not by dominant-negative mek1 plasmids. Immunoblotting revealed that RFB increased expression of phosphorylated AKT at concentrations that stimulated psca promoter activity, and that increased PSCA protein expression. In addition, RFB-dependent up-regulation of PSCA protein expression could be blocked by AKT inhibitors. These data demonstrate that RFB, and possibly other NSAID-like analogs, can increase expression of the psca gene both in vivo and in culture. They further suggest the utility of combining RFB with AKT inhibitors or with monoclonal antibodies targeting PSCA protein, for treatment or prevention of prostate cancer.
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PMID:Gene expression profiling in R-flurbiprofen-treated prostate cancer: R-Flurbiprofen regulates prostate stem cell antigen through activation of AKT kinase. 1694 54

Prostate stem cell antigen (PSCA) and prostate-specific antigen (PSA) are overexpressed in most prostate cancers. PSCA- and PSA-derived, HLA-A2 binding peptides are specific targets for T-cell responses in vitro. A phase I/II trial was performed to demonstrate feasibility, safety and induction of antigen-specific immunity by vaccination with dendritic cells (DC) presenting PSCA and PSA peptides in patients with hormone- and chemotherapy-refractory prostate cancer. Patients received 4 vaccinations with a median of 2.7 x 10(7) peptide-loaded mature DC s.c. in biweekly intervals. Clinical responses were assessed 2 weeks after the 4th vaccination. Immune monitoring was performed by DTH and HLA multimer analysis. Twelve patients completed vaccination without relevant toxicities. Six patients had stable disease after 4 vaccinations. One patient had a complete disappearance of lymphadenopathy despite rising PSA. Four patients with SD and 1 progressor developed a positive DTH after the 4th vaccination. With a median survival of all patients of 13.4 months, DTH-positivity was associated with significantly superior survival (p = 0.003). HLA tetramer analysis detected high frequencies of peptide-specific T cells after 2 vaccinations in 1 patient who was also the sole responder to concomitant hepatitis B vaccination as an indicator of immune competence and survived 27 months after start of vaccination. Vaccination with PSA/PSCA peptide-loaded, autologous DCs may induce cellular responses primarily in immunocompetent patients, which appear to be associated with clinical benefit. Testing of DC-based vaccination is warranted for patients at earlier stages of prostate cancer.
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PMID:Vaccination of advanced prostate cancer patients with PSCA and PSA peptide-loaded dendritic cells induces DTH responses that correlate with superior overall survival. 1697 30

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 murine 1G8 (micro1G8) monoclonal antibody directed against prostate stem cell antigen (PSCA) prevents prostate tumor establishment, growth, and metastasis in murine models. To further delineate in vivo targeting properties, micro1G8 was radiolabeled with In-111 and evaluated in nude mice bearing PC3-PSCA xenografts. Tumor activity ranged from 11.8% to 17.1% injected dose per gram (ID/g) at 24 to 96 hours postinjection. To extend the clinical applicability of micro1G8, a chimeric 1G8 antibody was produced that exhibited specific binding to PSCA and significant antitumor effect over micro1G8 in established LAPC-9 prostate cancer xenografts (P=0.0014). However, low expression yields and instability prompted us to humanize 1G8 by grafting the complementary determining regions onto the stable, human Fv framework of anti-p185 4D5v8 (trastuzumab). Two humanized 1G8 (hu1G8) versions (A and B) that differed in the number of murine residues present in the C-terminal half of CDR-H2, were produced. Biacore binding studies demonstrated affinities of 1.47 nM for micro1G8 and 3.74 nM for hu2B3-B, representing a 2.5-fold reduction. Tumor targeting of version B radioiodinated with I was evaluated by serial microPET imaging. Specific tumor targeting of I-hu1G8-B to PC3-PSCA [12.7 (+/-1.6)% ID/g at 94 h] and LAPC-9 [6.6 (+/-0.9)% ID/g at 168 h) xenografts was observed. Inhibition of tumor growth by hu1G8-B was demonstrated in mice bearing low-expressing SW-780-PSCA bladder carcinoma xenografts. In this model, the micro1G8 was ineffective, whereas the hu1G8-B exhibited approximately 50% inhibitory effect. These data support further development of hu1G8 anti-PSCA antibody for targeted imaging and therapy for tumors of urogenital origin.
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PMID:Targeting, imaging, and therapy using a humanized antiprostate stem cell antigen (PSCA) antibody. 1745 14

Targeted gene transduction to organs and tissues of interest is the ultimate goal of therapeutic gene delivery. Lentiviral vectors (LVs) are powerful tools for stable gene delivery but their integration into undesired cell types poses a serious safety concern for their use in the clinic. Here we report the development of a new dual-targeted LV that can preferentially home to and express in prostate cancer bone metastases in vivo after systemic delivery. Transductional targeting is mediated by a modified Sindbis virus envelope that interacts with the prostate stem cell antigen (PSCA) expressed by prostate cancer cells, and transcriptional targeting is mediated by a prostate cell specific promoter. Homing to prostate tumors was achieved in 70% of the animals. Importantly, tumors could be detected in some cases by molecular imaging prior to X-ray detection. The dual-targeted vector presents enhanced specificity with respect to individual transcriptional or transductional targeted vectors. Transgene expression in the liver was 190 times lower than the expression associated with solely transductionally targeted vectors, and there was 12 times less vector DNA than the amount present with solely transcriptionally targeted vectors. The LV presented here is a powerful tool for obtaining stable and site-specific gene expression and can be easily modified for its use in other diseases.
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PMID:A novel dual-targeted lentiviral vector leads to specific transduction of prostate cancer bone metastases in vivo after systemic administration. 1794 46


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