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

Monoclonal antibodies to human prostate adenocarcinoma membrane antigens were produced by fusion of P3X63/Ag8 mouse myeloma cells with spleen cells from BALB/c mice immunized against the prostate cancer cell line DU145. The hybrids were screened for antibody production using glutaraldehyde-fixed cells in a solid-phase radioimmunoassay. Antibody-binding specificity was also checked by quantitative adsorption, membrane immunofluorescence, and complement-dependent cytotoxicity assays. A hybridoma clone (83.21) was isolated that secreted antibodies which preferentially bound to several prostate and bladder cancer cell lines but did not bind to a variety of other normal and malignant human cell lines. This antibody also reacted with a cytomegalovirus-transformed human embryonic lung cell line but not to normal human embryonic lung cells. Quantitative adsorption studies demonstrated that the 83.21 monoclonal antibody was strongly reactive to membrane preparations from human prostate adenocarcinoma tissue and a liver metastasis of prostate carcinoma. Little or no binding activity was observed against two other prostate carcinomas, bening prostatic hyperplasia, normal prostate, or normal liver. Binding studies indicate that the 83.21 monoclonal antibody does not bind to alpha-fetoprotein, carcinoembryonic antigen, prostatic acid phosphatase, human leukocyte antigen, beta 2-microglobulin, HLA-Dr antigens, fibronectin, or prostate antigen. The data indicate that we have isolated a monoclonal antibody that binds to an antigen(s) expressed by several urogenital carcinoma cell lines as well as human prostate tumor tissue and that the antibody is not directed against well-known human tumor cell markers.
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PMID:Monoclonal antibodies to human prostate and bladder tumor-associated antigens. 704 15

Prostate cancer is the most common malignant tumour in men and there are few treatment options available once the tumour becomes refractory to hormonal manipulation. Prostate-specific antigen (PSA) is a secretory glycoprotein that is commonly expressed by prostatic epithelial cells and is found in elevated levels in the serum of men with prostate cancer. The identification of T cell specific epitopes within the coding sequence of PSA has led to the development of various vaccine strategies that target PSA in an attempt to treat established prostate cancer. These strategies have included human leukocyte antigen-restricted PSA peptides, dendritic cells pulsed with PSA, recombinant viruses expressing PSA and combinations of different vectors. In addition to PSA, several other antigens have been described that may be useful for targeting prostate tumours by vaccines. Animal studies have established the feasibility and safety for many of these agents and clinical trials are now in progress to evaluate the immunological and clinical responses of PSA vaccines. Further research in manipulating anti-PSA immunity with cytokines, costimulatory molecules and other immune modulating agents will likely improve the therapeutic effectiveness of PSA vaccines. Clinical trials designed to evaluate the effects of vaccination in different stages of disease and through different routes of administration need to be performed to define the optimal schedule for PSA vaccines in patients with prostate cancer, or for those at high risk of developing the disease.
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PMID:Prostate-specific antigen vaccines for prostate cancer. 1195 77

Prostate-specific antigen (PSA) is a potentially useful antigen for targeted T-cell immunotherapy of prostate cancer (CaP). Our laboratory has identified a synthetic nonamer peptide (PSA 146-154) homologue of PSA, which binds to the prevalent human leukocyte antigen, HLA-A2, and elicits specific cytotoxic T-lymphocyte (CTL) responses from normal individuals of the HLA-A2 phenotype. In the present study, we report on the induction of CTL from peripheral blood mononuclear cells (PBMC) of patients with hormone-refractory CaP, which exhibit the same specificity. T-cell lines were established from two patients by stimulation of PBMC with PSA 146-154 peptide in vitro. The T-cell lines exhibited specific cytolytic activity against T2 cells pulsed with PSA 146-154 peptide, but not a control HLA-A2 binding peptide (HIV-RT 476-484) via chromium release assay (CRA). The T-cell lines also showed PSA 146-154 peptide-specific IL-4 responses, but no detectable interferon-gamma (IFN-gamma) responses via enzyme-linked immuno-spot assays. Magnetic immuno-selection studies of one of the T-cell lines demonstrated that both cytolytic and interleukin-4 (IL-4) responses were mediated by CD8(+), but not by CD4(+) T cells. This Tc2 line was further characterized for the ability to recognize endogenously processed PSA epitopes. The line specifically secreted IL-4 in response to HLA-A2(+) target cells transfected to express PSA and specifically lysed the PSA(+) target cells, but not control transfected cells. The results indicate that the PSA 146-154 peptide emulates a naturally processed and presented peptide epitope of PSA that is within the T-cell repertoire of HLA-A2(+)patients with CaP.
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PMID:Induction of Tc2 cells with specificity for prostate-specific antigen from patients with hormone-refractory prostate cancer. 1207 Jul 13

To evaluate the safety and toxicity of peptide vaccination for patients with metastatic hormone-refractory prostate cancer (HRPC) based on pre-existing peptide-specific cytotoxic T-lymphocyte (CTL) precursors in the circulation, 10 patients positive for human leukocyte antigen (HLA)-A2 with metastatic HRPC were enrolled in a phase I study. Peptide-specific CTL-precursors reactive to 16 kinds of vaccine candidates in the pre-vaccination peripheral blood mononuclear cells (PBMCs) were measured, and patients were followed by vaccination with only positive peptides (up to 4 kinds of peptides). Serum prostate-specific antigen (PSA) levels were monitored regularly. The peptide vaccination was safe and well tolerated with no major adverse effects. The most common toxicities were dermatologic reactions at the injection site. Increased CTL response to peptides was observed in 4 of 10 patients. Anti-peptide IgG was also detected in post-vaccination sera of 7 of 10 patients. One patient showed the disappearance of a pelvic bone metastasis after five vaccinations. Three patients showed a decrease of serum PSA level from the baseline after the vaccination, but no patients showed a serum PSA level decrease of >/= 50%. The median survival duration of study patients was 22 months with follow-up from 3 to 27 months. We consider that the increase in cellular and humoral immune responses, and decrease in PSA level in some patients justify further development of peptide vaccination for metastatic HRPC patients.
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PMID:Phase I trial of patient-oriented vaccination in HLA-A2-positive patients with metastatic hormone-refractory prostate cancer. 1472 Mar 31

The HER2/neu protein is over-expressed in multiple epithelial tumors and the source of immunogenic peptides currently under investigation in vaccine trials in ovarian and breast cancers. We sought to define the correlation between HER2/neu expression and risk for prostate cancer recurrence and then determine the potential efficacy of anti-HER2/neu vaccination in prostate cancer patients at risk for recurrence. The risk for prostate-specific antigen (PSA) recurrence in 95 patients undergoing prostatectomy at the Walter Reed Army Medical Center (WRAMC) was calculated and correlated to HER2/neu expression, as determined by immunohistochemical staining. Peripheral blood lymphocytes (PBL) were then isolated from six consecutive human leukocyte antigen (HLA) A2+ patients with HER2/neu+ prostate tumors. These PBL were grown in parallel cultures and stimulated either with no peptide, HER2/neu E75 peptide, or control peptide. The cultures were compared for stimulated proliferation, induced peptide-specific cytotoxicity and tumor-specific cytotoxicity. When assessed by risk group, 69% of the high risk patients' tumors over-expressed HER2/neu compared to 47% of the intermediate risk group (p<0.05). Evaluation of the in vitro immune response of PBL isolated from six consecutive prostate cancer patients revealed a statistically significant increase in E75-stimulated lymphocytic proliferation. E75-stimulated lymphocytes demonstrated an E75-specific cytolytic response in 6/6 prostate cancer patients that increased with successive stimulations. Moreover, these E75-specific lymphocytes also demonstrated tumor-specific lysis against HER2/neu-expressing prostate cancer cell lines. The majority of prostate cancer patients at high risk for recurrence have HER2/neu expressing tumors. Hence, HER2/neu is a viable target for immunotherapeutics such as preventative immunization strategies with HER2/neu peptide vaccines.
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PMID:Preclinical testing of a peptide-based, HER2/neu vaccine for prostate cancer. 1554 16

The genetic transfer of antigen receptors is a powerful approach to rapidly generate tumor-specific T lymphocytes. Unlike the physiologic T-cell receptor, chimeric antigen receptors (CARs) encompass immunoglobulin variable regions or receptor ligands as their antigen recognition moiety, thus permitting T cells to recognize tumor antigens in the absence of human leukocyte antigen expression. CARs encompassing the CD3zeta chain as their activating domain induce T-cell proliferation in vitro, but limited survival. The requirements for genetically targeted T cells to function in vivo are less well understood. We have, therefore, established animal models to assess the therapeutic efficacy of human peripheral blood T lymphocytes targeted to prostate-specific membrane antigen (PSMA), an antigen expressed in prostate cancer cells and the neovasculature of various solid tumors. In vivo specificity and antitumor activity were assessed in mice bearing established prostate adenocarcinomas, using serum prostate-secreted antigen, magnetic resonance, computed tomography, and bioluminescence imaging to investigate the response to therapy. In three tumor models, orthotopic, s.c., and pulmonary, we show that PSMA-targeted T cells effectively eliminate prostate cancer. Tumor eradication was directly proportional to the in vivo effector-to-tumor cell ratio. Serial imaging further reveals that the T cells must survive for at least 1 week to induce durable remissions. The eradication of xenogeneic tumors in a murine environment shows that the adoptively transferred T cells do not absolutely require in vivo costimulation to function. These results thus provide a strong rationale for undertaking phase I clinical studies to assess PSMA-targeted T cells in patients with metastatic prostate cancer.
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PMID:Targeted elimination of prostate cancer by genetically directed human T lymphocytes. 1620 83

Prostatic acid phosphatase (PAP) is one of the prostate-related antigens that are applicable to specific immunotherapy for patients with prostate cancer. In this study, we determined whether or not PAP could be a target molecule in specific immunotherapy for patients with nonprostate cancer. A variety of adenocarcinoma cell lines were examined for their PAP expression at the mRNA and protein levels by reverse transcription polymerase chain reaction and western blot analysis, respectively. Considerable percentages of colon, gastric, and breast cancer cell lines were found to be positive for PAP at both the mRNA and the protein levels. The PAP expression in cancer tissues was also confirmed by immunohistochemical staining. In addition, we examined whether cancer-reactive cytotoxic T lymphocytes (CTLs) could be induced from peripheral blood mononuclear cells (PBMCs) of human leukocyte antigen (HLA) A24+ nonprostate cancer patients by in vitro stimulation with a PAP peptide. As a result, tumor-specific CTLs could be induced from the PBMCs of HLA-A24+ colon and gastric cancer patients. Their cytotoxicity against HLA-A24+ cancer cells was dependent on PAP peptide-specific and CD8+ T cells. These findings indicate that PAP could be a target molecule in specific immunotherapy for patients with nonprostate adenocarcinomas including colon and gastric cancers.
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PMID:Prostatic acid phosphatase as a target molecule in specific immunotherapy for patients with nonprostate adenocarcinoma. 1622 70

Tumors are highly robust and maintain their proliferative potential against both a wide range of host-defense mechanisms and anticancer therapies. In this study, we investigated the levels of human leukocyte antigen (HLA) class I, multi-drug resistance 1 (MDR1), and androgen receptor (AR) expressions in untreated prostate cancers harvested by radical prostectomy. The mean percentages of cancer cells expressing HLA class I, MDR1, and AR among the 10 cancer samples were 41, 35, and 74%, respectively. In addition, double-staining of HLA class I and MDR1 revealed the four definite populations (HLA class I(+)/MDR(+), HLA class I(+)/MDR(-), HLA class I (-)/MDR(+), and HLA class I(-)/MDR(-)) in cancer tissues from the majority of cancer patients tested, and the mean percentages of cells expressing these combinations were 13, 29, 22, and 38%, respectively. Similar results were obtained by double staining of HLA class I and AR, except for 2 cases in which HLA class I(-)/AR (+) cancer cells predominated. These results indicated that untreated prostate cancer cells acquired a wide range of genomic mutation, which may have been caused by internal host pressure to eliminate malignant cells, and would provide evidence of the robustness of untreated prostate cancer.
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PMID:[Acquired tumor "robustness" in the case of prostate cancer]. 1721 95

Tumors are highly robust and maintain their proliferative potential against a wide range of both host-defense mechanisms and anticancer therapies. One of the approaches to overcome cancer robustness could be combined therapy in which each modality imposes independent selective pressures against the acquired mutation of cancer. To develop such a therapy, it is crucial to understand the magnitude of acquired mutations. In this study, we investigated the levels of human leukocyte antigen (HLA)-class I, multidrug-resistance 1 (MDR1), and androgen receptor (AR) expressions in untreated prostate cancers harvested by radical prostatectomy. The mean percentages of cancer cells expressing HLA-class I, MDR and AR among the 10 cancer samples were 41, 35 and 74%, respectively. In addition, double-staining of HLA and MDR revealed the four definite populations (HLA+/MDR+, HLA+/MDR-, HLA-/MDR+ and HLA-/MDR-) in cancer tissues from the majority of cancer patients tested, and the mean percentages of cells expressing these combinations were 13, 29, 22 and 38%, respectively. Similar results were obtained by double-staining of HLA and AR, except for 2 cases in which HLA-/AR+ cancer cells predominated. These results indicated that untreated prostate cancer cells acquired a wide range of genomic mutations, which may have been caused by internal host pressure to eliminate malignant cells, and would provide evidence of the robustness of untreated prostate cancer.
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PMID:Differential levels of human leukocyte antigen-class I, multidrug-resistance 1 and androgen receptor expressions in untreated prostate cancer cells: the robustness of prostate cancer. 1761 54

The polycomb group protein enhancer of zeste homolog 2 (EZH2) is linked to aggressive prostate cancer and could be an appropriate target in specific immunotherapy. In this study, we attempted to identify EZH2-derived peptides that have the potential to generate cancer-reactive cytotoxic T lymphocytes (CTLs) in human leukocyte antigen (HLA)-A2+ prostate cancer patients. Twelve EZH2-derived peptides were prepared based on the HLA-A2 binding motif. These peptide candidates were screened first by their ability to be recognized by immunoglobulin G (IgG), and then by their ability to induce peptide-specific cytotoxic T lymphocytes (CTLs). As a result, five EZH2 peptides recognized by IgG (EZH2 120-128, EZH2 165-174, EZH2 569-577, EZH2 665-674, and EZH2 699-708) were frequently detected in the plasma of prostate cancer patients. Among them, the EZH2 120-128 and EZH2 165-174 peptides effectively induced HLA-A2-restricted and cancer-reactive CTLs from prostate cancer patients. The cytotoxicity was mainly dependent on EZH2 peptide-specific and HLA-A2-restricted CD8+ T cells. These results indicate that these EZH2 120-128 and EZH2 165-174 peptides could be promising candidates in peptide-based immunotherapy for HLA-A2+ prostate cancer patients.
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PMID:New peptides of the polycomb group protein enhancer of zeste homolog 2 with the potential to induce cancer-reactive cytotoxic T lymphocytes in human leukocyte antigen-A2+ prostate cancer patients. 1791 78


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