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)

D-RNAi (Messenger RNA-antisense DNA interference), a novel posttranscriptional phenomenon of silencing gene expression by transfection of mRNA-aDNA hybrids, was originally observed in the effects of bcl-2 on phorbol ester-induced apoptosis in human prostate cancer LNCaP cells. This phenomenon was also demonstrated in chicken embryos and a human CD4(+) T cell line, H9. The in vivo transduction of beta-catenin D-RNAi was shown to knock out more than 99% endogenous beta-catenin gene expression, while the in cell transfection of HIV-1 D-RNAi homolog rejected viral gene replication completely. D-RNAi was found to have long-term gene knockout effects resulting from a posttranscriptional gene silencing mechanism that may involve the homologous recombination between intracellular mRNA and the mRNA components of a D-RNAi construct. These findings provide a potential intracellular defense system against cancer and viral infections.
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PMID:D-RNAi (messenger RNA-antisense DNA interference) as a novel defense system against cancer and viral infections. 1218 82

All of these studies taken together highlight key areas that must be addressed in the future in order for the field to continue to move forward. These issues are many, including but not limited to method of delivery of dendritic cells to patients, maturation status of the dendritic cells, and methods of monitoring responses to these vaccines. Each of these requires some comment. Different strategies of immunization were used in these studies. DCs were injected at various times and in various locations, including intradermally/subcutaneously, intranodally, and intravenously. Investigation of the pattern of spread of subcutaneously injected fluorescently labeled DCs in the chimpanzee was studied at the University of Pittsburgh. Although rodent DCs had previously been shown to remain at the site of injection, these immature primate DCs migrated to draining lymph nodes and interact appropriately with T cells for as long as 5 days after administration. Data not shown in the same study reveal that intravenously administered DCs were undetectable in draining lymph nodes. Two groups have undertaken evaluation of route of administration of DCs in humans. The first of these examined migration of immature, indium-111-labeled dendritic cells after RNA-loading in metastatic cancer patients [44]. The DCs were injected either intravenously, subcutaneously, and intradermally. Only DCs injected intradermally were cleared from the injection site with migration to regional lymph nodes. The immunologic significance of these findings is unclear, however. Another study examined this issue by studying prostatic acid phosphatase (PAP) protein-loaded mature DCs injected intravenously, intradermally, and intralymphatically in prostate cancer patients [45]. Regardless of route of administration, T cell responses were induced as measured by proliferation when PBMCs in vitro were stimulated with the PAP protein. Cytokine analysis of the patients revealed that the majority of patients undergoing either intralymphatic or intradermal injection had increases in measurable interferon-gamma but that none of the intravenously-injected patients did. The intralymphatic and intradermal routes thus seem to lead to stronger Th1 responses. But no data was presented regarding the numbers of PAP precursors induced by vaccination nor their specificity/cytotoxicity. Another issue in DC administration that should also affect route of administration is maturation status of the dendritic cells. Many of the studies used immature dendritic cells to immunize patients whereas others used mature cells. A number of studies have demonstrated that maturation signals such as inflammatory cytokines and CD40 ligation lead to down-regulation of antigen processing and up-regulation of the chemokine receptor CCR7, which leads to homing to lymph nodes [46] as well as the MHC molecules, costimulatory molecules, and maturation markers [8,47,48]. In addition, different maturation agents and sequences of addition of these maturation agents may lead to differences in functions of dendritic cells [48-51]. Others have found that injection of immature DCs pulsed with influenza matrix peptide and KLH, and lead to greater numbers of influenza-specific T cells, but these cells had reduced interferon-gamma production and lacked killer activity [52]. Perhaps the most impressive results in a clinical trial, however, were gained by injecting similar cells loaded with melanoma peptides [21]. In addition, sequence of loading and maturation may be important in creating vaccines. One study using CEA peptides and CEA RNA found that optimal T cell presentation occurs when peptides are loaded after maturation with CD40 ligand and when RNA is transfected before maturation with CD40 ligand [53]. As all of these studies reveal, more investigation into the role of DC maturation as well as its timing and sequence is needed. Finally, a multitude of methods to detect response to vaccination have been attempted in all of the above studies. Many use DTH responses, but these may measure CD4 T cells instead of CD8 T cells. The availability of tetramers allows easier quantification of CTL precursors, but they provide no assessment of the function of these T cells. Enzyme-linked immunospot assays allow identification and quantification of numbers of cells producing cytokines such as interferon-gamma when encountering target antigens, but cytokine production may not correlate with tumor cell killing. Chromium release assays or flow cytometric assays for molecules such as perforin may be used to validate killing, but inability of many tumors to grow in vitro precludes direct assessment of tumor cell killing via this method. Other responses in human subjects may also be measured. Some of the cited studies yielded clinical responses that could be measured via physical examination or radiologic study. This is the exception rather than the rule, however. Others have monitored the decrease in serum tumor markers such as PSA or CEA. But these may not correlate directly with tumor burden. Indirect calculation of tumor burden by using quantitative PCR to estimate the number of circulating tumor cells in peripheral blood may be promising in this regard. Despite the lack of consensus as to what constitutes an effective response, most would agree that monitoring of these patients should include measures of both immunologic response and clinical tumor effect. All of this leads to the conclusion that DC-based cancer vaccines have progressed a great deal but that much work still needs to be done. Only rigorous bench top experimentation followed by careful patient selection and vaccine administration, and then by meticulous patient monitoring, will lead to advances in the field.
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PMID:Dendritic cell gene therapy. 1248 60

Osteocalcin (OC), a major noncollagenous bone matrix protein, is expressed prevalently in prostate cancer epithelial cells, adjacent fibromuscular stromal cells, and osteoblasts in locally recurrent prostate cancer and prostate cancer bone metastasis [Matsubara, S., Wada, Y., Gardner, T.A., Egawa, M., Park, M.S., Hsieh, C.L., Zhau, H.E., Kao, C., Kamidono, S., Gillenwater, J.Y., and Chung, L.W. (2001). Cancer Res. 61, 6012-6019]. We constructed an adenovirus vector carrying osteocalcin promoter-driven herpes simplex virus thymidine kinase (Ad-OC-hsv-TK) to cotarget prostate cancer cells and their surrounding stromal cells. A phase I dose escalation clinical trial of the intralesional administration of Ad-OC-hsv-TK followed by oral valacyclovir was conducted at the University of Virginia (Charlottesville, VA) in 11 men with localized recurrent and metastatic hormone-refractory prostate cancer (2 local recurrent, 5 osseous metastasis, and 4 lymph node metastasis) in order to determine the usefulness of this vector for the palliation of androgen-independent prostate cancer metastasis. This is the first clinical trial in which therapeutic adenoviruses are injected directly into prostate cancer lymph node and bone metastasis. Results show that (1). all patients tolerated this therapy with no serious adverse events; (2). local cell death was observed in treated lesions in seven patients (63.6%) as assessed by TUNEL assay, and histomorphological change (mediation of fibrosis) was detected in all posttreated specimens; (3). one patient showed stabilization of the treated lesion for 317 days with no alternative therapy. Of the two patients who complained of tumor-associated symptoms before the treatment, one patient with bone pain had resolution of pain, although significant remission of treated lesions was not observed by image examination; (4). CD8-positive T cells were predominant compared with CD4-positive T cells, B cells (L26 positive), and natural killer cells (CD56 positive) in posttreated tissue specimens; (5). levels of HSV TK gene transduction correlated well with coxsackie-adenovirus receptor expression but less well with the titers of adenovirus injected; and (6). intrinsic OC expression and the efficiency of HSV TK gene transduction affected the levels of HSV TK protein expression in clinical specimens. Our data suggest that this form of gene therapy requires further development for the treatment of androgen-independent prostate cancer metastasis although histopathological and immunohistochemical evidence of apoptosis was observed in the specimens treated. Further studies including the development of viral delivery will enhance the efficacy of Ad-OC-hsv-TK.
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PMID:Phase I dose escalation clinical trial of adenovirus vector carrying osteocalcin promoter-driven herpes simplex virus thymidine kinase in localized and metastatic hormone-refractory prostate cancer. 1263 3

An effective tumor vaccine may require the induction of both CTL and T-helper (Th) cell responses against tumor-associated antigens. Human telomerase reverse transcriptase (hTERT) is highly expressed in >85% of cancer cells and thus is a potential target for tumor vaccines. We therefore sought to identify promiscuous Th epitopes in hTERT, which can be presented by more than one MHC class II allele. Each of 10 peptides derived from hTERT that were predicted to bind to MHC class II molecules was found to be able to induce primary human T-cell responses in vitro. We then established CD4(+) T-cell clones specific for these peptides and found that only hTERT(766) (LTDLQPYMRQFVAHL)-specific CD4(+) Th cells were effective in recognizing naturally processed hTERT antigen. We further found that the naturally processed epitopes hTERT(766) and hTERT(672) (which was identified previously) were promiscuous and capable of inducing CD4(+) T-cell responses in the context of several commonly found HLA-DR alleles, including DR1, DR7, and DR15 for hTERT(672), and DR4, DR11, and DR15 for hTERT(766). We further demonstrated that immunization of humanized HLA-DR4 transgenic mice with hTERT(766) peptide elicited antigen-specific Th responses that can recognize the antigenic peptides derived from hTERT protein and various hTERT-positive tumors, such as breast cancer, melanoma, and leukemia. It was also shown that T-cell precursors specific for the naturally processed epitopes are part of the T-cell repertoires in healthy donors and prostate cancer patients. Thus, these promiscuous, naturally processed Th epitopes in hTERT could be used to develop improved cancer vaccines through the simultaneous stimulation of CTL and Th cells against a broad spectrum of hTERT-positive tumors.
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PMID:Human telomerase reverse transcriptase-specific T-helper responses induced by promiscuous major histocompatibility complex class II-restricted epitopes. 1458 45

A novel orthotopic metastatic model of mouse prostate cancer was developed using MHC-negative TRAMP-C1P3 (transgenic adenocarcinoma of mouse prostate) cells derived by serial passage of the parental TRAMP-C1 line in mouse prostate glands. TRAMP-C1P3 cells grew efficiently in mouse prostate glands and reproducibly metastasized to draining lymph nodes. Using this model, we show that Fms-like tyrosine kinase-3 ligand (flt3-L) dramatically inhibited growth of preexisting orthotopic TRAMP-C1P3 tumors and the development of metastatic disease. Mice remained in remission for several months following termination of flt3-L treatment but eventually relapsed and died of progressive disease. flt3-ligand treatment induced a pronounced mixed inflammatory cell infiltrate that consisted of CD8alpha-CD4- dendritic cells (CD11c+), macrophages, granulocytes (Gr-1+) and to a lesser extent T cells (CD4+ and CD8+). Dendritic cells isolated from TRAMP-C1P3 tumors were phenotypically immature (CD11c+ B7.2-I-A-CD40-), and this phenotype was also predominant in peripheral organs of mice treated with flt3-L alone or in combination with the DC maturation factor, CD40-L. Diminished expression of TCR-beta, CD3-epsilon, and CD3-zeta was also observed on intratumoral T cells, although these signaling proteins were reexpressed following in vitro culture with IL-2. The TCR/CD3 complex remained intact on peripheral T cells except in mice treated with flt3-L where CD3-zeta loss was observed. In contrast to alphabeta-T cells, tumor-infiltrating gammadelta-T cells maintained expression of their antigen receptors but not CD3epsilon. Thus, TRAMP-C1P3 tumors quickly establish a microenvironment that profoundly diminishes expression of molecules critical for normal dendritic cell and T cell function, thus limiting the efficacy of flt3-L and CD40-L immunotherapy. Overall, these data suggest that long-term cures of established MHC-negative tumors may not be achieved until therapeutic interventions are engineered to overcome this immunosuppressive microenvironment.
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PMID:Prostate tumor microenvironment alters immune cells and prevents long-term survival in an orthotopic mouse model following flt3-ligand/CD40-ligand immunotherapy. 1467 30

In order to develop immunotherapies for prostate cancer, many groups are exploring vaccination strategies to induce an immune response against prostate specific antigen (PSA). To determine if T-cell recognition of PSA might be a feature of a naturally occurring human disease, we have studied patients with prostatitis, a poorly understood clinical syndrome of men in which there is evidence that an immune response directed against the prostate may be occurring. We wished to determine if a T-cell response to PSA might be occurring in these patients. We generated long-term T-cell lines from peripheral blood mononuclear cells (PBMC) of one patient with granulomatous prostatitis using purified PSA as an antigen. Several CD4+ and CD8+ TcR alpha/beta+ T-cell lines were selected for PSA reactivity as measured by at least a threefold increase in IFN-gamma secretion in response to PSA presented by irradiated autologous PBMC. CD4 and CD8 T-cell lines recognized PSA in the context of HLA-DRbeta1*1501 and HLA-B*0702, respectively. The specificity and HLA restriction of the lines was confirmed using EBV-B cell lines infected with a recombinant PSA-expressing vaccinia virus and also engineered to express PSA by retroviral transfection. HLA-matched targets infected by control vector as well as HLA-mismatched PSA-expressing targets did not induce the response. The data demonstrate that PSA-specific T cells are present in the PBMC of this patient with granulomatous prostatitis, who may be manifesting naturally the type of immune response directed at the prostate that is the goal of prostate cancer immunotherapy. However, the Class I-restricted epitope has not yet been demonstrated to be expressed on the surface of prostate cancer cells. To our knowledge, this is the first demonstration of HLA-DRB1*1501- or HLA-B*0702-restricted responses to PSA and extends the number of HLA molecules accommodating the use of PSA antigen as a candidate vaccine for prostate cancer immunotherapy.
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PMID:CD4 and CD8 T-lymphocyte recognition of prostate specific antigen in granulomatous prostatitis. 1597 30

MUC-1 is overexpressed on many tumor cells. In addition, aberrant glycosylation of MUC-1 on human tumors leads to exposure of cryptic peptide epitopes that play a role in tumor immunity. As such, it has been identified as a potential target for immunotherapy. The purpose of this phase 1 clinical trial was to determine the maximum tolerated dose, safety of a multiple-dose regimen, and the immunologic effect of vaccinia virus expressing MUC-1 and IL-2 genes (VV/MUC-1/IL-2) in patients with advanced prostate cancer. Five x 10(5), 5 x 10(6), and 5 x 10(7) plaque-forming units (pfu) of vaccinia viruses were used in the dose-escalating study. Viruses were given via intramuscular injection, and clinical response and immune function modulation were analyzed. No grade 3 or 4 toxicity was observed. Objective clinical response was observed after the fourth injection (0.3 ng/mL) in only one patient who received an intermediate dose of virus. Systemic immune modulation in this patient included (1) up-regulation of IL-2 (CD25) and T cell (TcR alphabeta) receptors, (2) increase in the CD4/CD8 ratio (2.5-fold) (3) augmentation of T-helper type 1 cell (TH1) (interferon-gamma and tumor necrosis factor-alpha) but not TH2 (IL-4) cytokine mRNA expression, (4) induction of natural killer cell activity and MHC independent MUC-1 specific cytotoxic T-cell activity, and (5) normalization of mRNA expression of T-cell-associated signal transduction molecules TcR-zeta and p56lck. These results suggest that VV/MUC-1/IL-2 gene therapy with a maximum tolerated dose of 5 x 10(7) pfu is safe and well tolerated.
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PMID:Phase I trial of antigen-specific gene therapy using a recombinant vaccinia virus encoding MUC-1 and IL-2 in MUC-1-positive patients with advanced prostate cancer. 1507 42

Immunization of cancer patients is most effective in tumor-free conditions or in the presence of minimal residual disease. In the attempt to develop new strategies able to control tumor recurrence while allowing the development of protective immunity, we have investigated the immunogenic potential of two distinct vaccine formulations when provided alone or upon single and repeated treatment with chemotherapeutics drugs. Vaccine-induced T cell responses were first investigated by tracing Ag-specific T cell responses in mice bearing detectable frequencies of Ag-specific TCR transgenic CD4 and CD8 T cells. These studies indicated that immunization with peptide-pulsed dendritic cells and soluble Ag plus adjuvant elicited a comparable expansion and differentiation of CD4 and CD8 effector cells in the peripheral lymphoid tissues when provided alone or shortly after Doxorubicin or Melphalan administration. We also analyzed the potency of the combined vaccination in transgenic adenocarcinoma mouse prostate mice, which develop spontaneous prostate cancer. Dendritic cell-based vaccination elicited potent tumor-specific cytotoxic responses in mice bearing prostate intraepithelial neoplasia both in the absence and in the presence of Doxorubicin. Together our results indicate that Doxorubicin- or Melphalan-based chemotherapy and Ag-specific vaccination can be combined for adjuvant treatments of cancer patients.
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PMID:The immunogenicity of dendritic cell-based vaccines is not hampered by doxorubicin and melphalan administration. 1574 63

BAT is an immune-activating monoclonal antibody produced against Daudi cell membranes and selected for stimulating lymphocyte proliferation. The anti-tumor activity of BAT is related to its immunostimulatory properties. Both T and NK cells mediate the anti-tumor activity of BAT. CD4-positive T cells respond to BAT activation by proliferation and INF-gamma production. The aim of the study was to assess the probability that the BAT monoclonal antibody binding capacity to T cells is a marker for different cancers. Human peripheral blood T cells from colon, breast and prostate cancer patients, as well as healthy volunteer donors, were tested for the percentage of binding to BAT mAb (BAT/CD3 cells) by FACS analysis. All patients were tested before undergoing surgery or treatment, and their diagnosis was confirmed by histology. The results showed that the percentage of BAT monoclonal antibody binding to CD3-positive T cells in the peripheral blood was different in cancer patients with diverse tumor types. We found that lymphocytes from the blood of healthy donors contained 25% BAT/CD3 cells. In colon and breast cancer patients, a significant decrease to 13 and 11% of BAT/CD3 cells was found. In contrast, these cells increased ><50% in patients with prostate cancer. These findings may have a potential diagnostic significance and also assist in the evaluation of strategies for the therapeutic use of BAT for different cancer patients.
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PMID:Cancer disease predictive diagnosis: BAT/CD3-positive lymphocytes in cancer patients. 1575 91

To understand the T cell response to prostate cancer, we created transgenic mice that express a model antigen in a prostate-restricted pattern and crossed these animals to TRAMP mice that develop spontaneous prostate cancer. Adoptive transfer of prostate-specific CD4 T cells shows that, in the absence of prostate cancer, the prostate gland is mostly ignored. Tumorigenesis allows T cell recognition of the prostate gland--but this recognition is tolerogenic, resulting in abortive proliferation and ultimately in hyporesponsiveness at the systemic level. Androgen ablation (the most common treatment for metastatic prostate cancer) was able to mitigate this tolerance--allowing prostate-specific T cells to expand and develop effector function after vaccination. These results suggest that immunotherapy for prostate cancer may be most efficacious when administered after androgen ablation.
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PMID:Androgen ablation mitigates tolerance to a prostate/prostate cancer-restricted antigen. 1576 62


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