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)

Adenovirus-based gene therapy may provide an alternative mode of treatment for prostate cancer, especially for late-stage and androgen-independent disease for which there is currently no effective treatment. Efficient adenovirus infection of target cells depends upon the presence of the coxsackie adenovirus cell surface receptor, CAR, which is the primary receptor for group C adenoviruses and is important for the attachment of adenovirus to the cell membrane. To evaluate the potential efficacy of adenoviral therapy for prostate cancer, we evaluated CAR expression in normal prostate tissue and in prostate carcinoma of increasing Gleason grades in paraffin-embedded, archival tissues using a polyclonal antibody raised against human CAR. Immunohistochemical analysis of benign prostate epithelia demonstrated intense luminal and lateral cell membrane staining. There was a statistically significant difference in CAR membrane expression with respect to Gleason score. In addition, metastatic prostate specimens demonstrated strong membrane staining for CAR. Adenovirus therapy may, therefore, provide an alternate modality in the treatment of prostate cancer and may be especially efficacious in the treatment of metastatic disease.
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PMID:Expression of the coxsackie adenovirus receptor in normal prostate and in primary and metastatic prostate carcinoma: potential relevance to gene therapy. 1209 94

Bone remains one of the major sites, and most lethal host organs, for prostate cancer metastasis. Prostate cell spread and establishment in bone depends on multiple reciprocal modifications of bone stromal and epithelial cancer cell behaviors. This review focuses on recent advances in the characterization of cell-cell and cell-matrix interplay, effects on cell growth, adhesion and invasion, and several therapeutic possibilities for co-targeting prostate cancer cells and bone stroma. We address the topic from three main perspectives: (1) the normal and aging bone stromal environment, (2) the "reactive" bone stromal environment, and (3) the cancerous prostate epithelial cells themselves. First, normal, and especially aging, bones provide uniquely rich and "fertile soil" for roaming cancer cells. The interactions between prostate cancer cells and insoluble extracellular matrices, soluble growth factors, and/or sex steroid hormones trigger bone remodeling, through increased osteoclastogenesis and furthur matrix metalloproteinase activity. Second, after cancer cell arrival and establishment in the bone, host stromal cells respond, becoming "reactive" in a process again involving extracellular matrix remodeling, together with growth factor and steroid receptor signaling this process ultimately enhances cancer cell migration, stromal transdifferentiation, and invasion of the cancer tissues by stromal, inflammatory, and immune-responsive cells. Third, prostate cancer cells also respond to supportive bone microenvironments, where soluble and matrix-associated molecules affect cancer cell growth and gene expression, especially altering cancer cell surface receptor and integrin-mediated cell signaling. We discuss both integrin cell-matrix and gap junctional cell-cell communication between cancer cells and their microenvironments during prostate cancer progression.
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PMID:Modulation of prostate cancer growth in bone microenvironments. 1499 61

The p75neurotrophin receptor (p75NTR) has been characterized as a tumor suppressor in human prostate cancer. Ectopic re-expression of this cell surface receptor protein in prostate cancer cell lines has been shown to increase the frequency of apoptosis and concurrently reduce the rate of cellular proliferation. Since it is difficult to maintain a therapeutic level of this membrane receptor protein by systemic administration in the blood, we utilized an alternative gene therapy strategy based upon intra-tumoral injection into xenografts of PC-3 prostate tumor cells of a lipoplex containing the p75NTR gene. Administration of the p75NTR gene into subcutaneous PC-3 xenografts suppressed in a dose-dependent manner the growth of tumors. Within the gene therapy-treated tumors, re-expression of the p75NTR gene product was associated with increased apoptosis and reduced proliferation of tumor cells. These results suggest that the p75NTR may be a suitable candidate for gene therapy of prostate cancer cells.
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PMID:Gene therapy of prostate xenograft tumors with a p75NTR lipoplex. 1551 7

Activation of cell surface components has been implicated in the activation of downstream signaling cascade in response to UV irradiation, and yet the identity and the interaction of those components have been scantly documented. Accumulating evidence indicates that caveolae encapsulating caveolins is the location for those interactions. We found in cultured human keratinocytes that UV irradiation induced both caveolin-1 and EGFR phosphorylation. Filipin, a caveolae disruptive agent, inhibited UV-induced caveolin-1 activation. Na+-K+-ATPase catalyzes active transport of Na+ and K+ across plasma membrane of mammalian cells, inactivation of which has recently been shown to be involved in the activation of signal transduction pathways including MAP kinase cascade. We found in this study that UV inactivated Na+-K+-ATPase in time-dependent manner, Na+-K+-ATPase activity started to decrease 5 min post UV irradiation and reduced to 60% of its original activity within 1 h. Pretreatment with Flipin and MMP inhibitor recovered Na+-K+-ATPase activity lost by UV irradiation. ECIS analysis indicated that both EGF treatment and UV irradiation increased membrane electric activity which was inhibited by MMP inhibitor and Filipin. Further study showed that pretreatment of human keratinocytes with MMP inhibitor or Filipin inhibited UV-induced phosphorylation of p38 and JNK, which was however not observed in LnCap cells, a prostate cancer cell line lacking caveolin-1. UV irradiation also induced ectodomain shedding of HB-EGF in a time-dependent manner in keratinocytes. Collectively, we conclude that UV-induced MAP kinase activation is mediated by cell surface receptor activation due to the matrix activity and membrane caveolae function and inactivation of Na+-K+-ATPase.
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PMID:Extracellular matrix activity and caveolae events contribute to cell surface receptor activation that leads to MAP kinase activation in response to UV irradiation in cultured human keratinocytes. 1575 25

The present study evaluated a hull-volume definition strategy for the planning organ at risk volume (PRV) for the rectum in the planning of radiotherapy of prostate cancer. The bounding volumes of rectum contours of 1 to 5 CT scans were compared on the basis of the rectum coverage probabilities for 5 patients. In addition, IMRT treatment plans were optimized using the rectum hull PRV5 of 5 CTs and each of the conventional rectum contours PRV1. The plans were compared on the basis of the organ doses caused by the individual organ motion. PRV5 allowed to cover the rectum with a probability of nearly 90% (PRV1 67%). Rectal wall dose showed a great variability for PRV1, while planned and treatment dose agreed well for PRV5 due to the improved geometric information which resulted in a better rectal sparing. In conclusion, the rectum hull-volume PRV5 is a well suited PRV for planning of IMRT dose distributions allowing dose escalation as well as rectal sparing.
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PMID:[Dosimetric consequences of the application of a rectum hull-planning volume for treatment planning of intensity modulated radiotherapy of prostate cancer]. 1698 60

Several monoclonal antibodies that target cell surface receptors have gained approval by the U.S. Food and Drug Administration and are widely used in the treatment of some cancers. These include but are not limited to the anti-CD20 antibody Rituximab, used in lymphoma treatment, as well as anti-HER-2 antibody for breast cancer therapy. The efficacy of this cancer immunotherapy modality is, however, limited by the large size of the antibody (160 kd) and its relatively nonspecific binding to the reticuloendothelial system. This latter property is particularly problematic if the antibody is used as a vehicle to deliver radionuclides, cytotoxic drugs, or toxins to the tumor site. Peptides, peptidomimetic, or small molecules are thus attractive as alternative cell surface targeting agents for cancer imaging and therapy. Cancer cell surface targeting peptides can be derived from known native peptide hormones such as somatostatin and bombesin, or they can be identified through screening combinatorial peptide libraries against unknown cell surface receptor targets. Phage-display peptide library and one-bead one-compound (OBOC) combinatorial library methods have been successfully used to discover peptides that target cancer cells or tumor blood vessel endothelial cells. The phage-display peptide library method, because of its biological nature, can only display l-amino acid peptides. In contrast, the OBOC combinatorial library method allows for bead-surface display of peptides that contain l-amino acids, d-amino acids, unnatural amino acids, or other organic moieties. We have successfully used the OBOC method to discover and optimize ligands against unique cell surface receptors of prostate cancer, T- and B-cell lymphoma, as well as ovarian and lung cancers, and we have used some of these peptides to image xenografts in nude mice with high specificity. Here, we (i) review the literature on the use of phage-display and OBOC combinatorial library methods to discover cancer and tumor blood vessel targeting ligands, and (ii) report on the use of an ovarian cancer targeting ligand, OA02, as an in vivo PET imaging probe in a xenograft model in nude mice.
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PMID:From combinatorial chemistry to cancer-targeting peptides. 1788 Jan 66

Retroviral and lentiviral vectors are effective gene delivery vehicles that are being evaluated in clinical trials. Variations in the viral envelope (Env) glycoproteins, which are used to pseudotype retroviral or lentiviral vectors, can alter vector performance, including stability, titers, host range, and tissue tropism. Xenotropic murine leukemia virus (MLV)-related virus (XMRV) is a novel human retrovirus identified in patients with prostate cancer. XMRV targets XPR1 cell surface receptor, which is expressed in a broad range of human tissues including hematopoietic stem cells. Pseudotyping with XMRV Env would allow targeting of XPR1-expressing tissues. Here, we characterized XMRV Env-pseudotyped retroviral and lentiviral vectors. Although HIV and MLV vectors were poorly pseudotyped with wild-type XMRV Env, replacement of the C-terminal 11 amino acid residues in the transmembrane domain of XMRV Env with the corresponding 6 amino acid residues of amphotropic MLV Env (XMRV/R(ampho)) significantly increased XMRV Env-pseudotyped HIV and MLV vector titers. The transduction efficiency in human CD34(+) cells when using the XMRV/R(ampho)-pseudotyped HIV vector (10-20%) was comparable to that achieved when using the same infectious units of vesicular stomatitis virus G glycoprotein-pseudotyped vector (25%); thus the modified XMRV Env offers an alternative pseudotyping strategy for XPR1-mediated gene delivery.
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PMID:Characterization of retroviral and lentiviral vectors pseudotyped with xenotropic murine leukemia virus-related virus envelope glycoprotein. 2050 33

Interaction of epithelial cells with basement membrane (BM) is mediated by cell-adhesion molecules, which regulate cell proliferation, motility, and differentiation by integrating signals from extracellular matrix and soluble factors. alpha-Dystroglycan (alpha-DG) is one of the most important adhesion molecules in epithelial cell-BM interaction. alpha-DG serves as the cell surface receptor for several major BM proteins, including laminin, perlecan, and agrin. The laminin G-like domain in all these proteins binds to a unique glycan structure, so-called laminin-binding glycan, attached to alpha-DG with high affinity. Formation of the laminin-binding glycan is required for the BM assembly, and loss or deficiency of the glycan causes muscular dystrophy. We studied the role of this alpha-DG-specific glycan modification in tumor development, and identified a tumor suppressor function of the laminin-binding alpha-DG. In this chapter, we describe methods used to isolate the cell populations from human prostate cancer cell line PC3 and characterize their potentials in tumor formation and metastasis in vitro and in vivo.
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PMID:A tumor suppressor function of laminin-binding alpha-dystroglycan. 2081 78

G protein-coupled receptors, the largest cell surface receptor family, have emerged as critical players in cell death and survival. High gene expression level of the G(q)-coupled P2Y(1) nucleotide receptor in PC-3 prostate cancer cells was demonstrated using real-time quantitative PCR and confirmed by Western blotting and confocal laser scanning microscopy. A selective P2Y(1) receptor agonist, the ADP analogue MRS2365, concentration-dependently induced intracellular calcium mobilization (EC(50) 5.28nM), which was diminished by P2Y(1) receptor-selective antagonist MRS2500. P2Y(1) receptor activation by MRS2365 induced apoptosis in assays of Caspase-3, LDH release, and annexin-V staining. The pro-apoptotic effect of MRS2365 was blocked by MRS2500, P2Y(1) siRNA, and an inhibitor of the MAP kinase pathway PD98059. MRS2365 significantly inhibited the proliferation of PC-3 cells, examined using a MTT assay. Thus, activation of the P2Y(1) receptor induced cell death and inhibited growth of human prostatic carcinoma PC-3 cells. Activation of the P2Y(1) receptor should be a novel and promising therapeutic strategy for prostate cancer.
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PMID:Activation of the P2Y1 receptor induces apoptosis and inhibits proliferation of prostate cancer cells. 2163 28

Many tumors highly express specific populations of G-protein-coupled receptors (GPCRs) that could be utilized for receptor-targeted therapy. We confirmed significant quantities of mRNAs specific for certain somatostatin (SST), vasoactive intestinal peptide (VIP), and bombesin (BN) receptors in various commercially available tumor cell lines. Very few of the tumor cell lines examined displayed the high receptor-binding affinity despite exhibiting the expression of appropriate mRNAs and proteins of the cognate receptors. However, binding assays establish that some tumor cell lines, such as pancreatic cancer CFPAC-1, prostate cancer DU-145, and pancreatic carcinoid BON, demonstrate high BN receptor binding. BON cells also demonstrate high somatostatin receptor (SSTR) affinity binding. We also found that tumor cell lines, such as BON and host cells expressing SST receptor subtypes 1 or 2 (CHO-R1 or CHO-R2), underwent a decrease in cell surface receptor density in multiple passages. BON and CHO-R2 cells also rapidly internalize a significant proportion of cell surface ligand-receptor complexes. The tumor cells CFPAC-1, DU-145, and BON with high receptor binding could be useful for peptide drug studies. BON cells were further applied to test SST/BN analogs and cytotoxic conjugates. Furthermore, the in vivo antitumor assay showed that the cytotoxic conjugate CPT-SST targeting all SSTR subtypes displayed a potent tumor-suppressive ability to BON tumors expressing multiple SSTR subtypes.
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PMID:Investigation of cancer cell lines for peptide receptor-targeted drug development. 2183 Sep 41


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