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)

Molecular therapy, including gene therapy, is a promising strategy for the treatment of human disease. However, delivery of molecular therapeutics efficiently and specifically to the target tissue remains a significant challenge. A human transferrin (Tf)-targeted cationic liposome-DNA complex, Tf-lipoplex, has shown high gene transfer efficiency and efficacy with human head and neck cancer in vitro and in vivo (Xu, L., Pirollo, K.F., Tang, W.H., Rait, A., and Chang, E.H. Hum. Gene Ther. 1999;10:2941-2952). Here we explore the structure, size, formation process, and structure-function relationships of Tf-lipoplex. We have observed Tf-lipoplex to have a highly compact structure, with a relatively uniform size of 50-90 nm. This nanostructure is novel in that it resembles a virus particle with a dense core enveloped by a membrane coated with Tf molecules spiking the surface. More importantly, compared with unliganded lipoplex, Tf-lipoplex shows enhanced stability, improved in vivo gene transfer efficiency, and long-term efficacy for systemic p53 gene therapy of human prostate cancer when used in combination with conventional radiotherapy. On the basis of our observations, we propose a multistep self-assembly process and Tf-facilitated DNA cocondensation model that may provide an explanation for the resultant small size and effectiveness of our nanostructural Tf-lipoplex system.
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PMID:Self-assembly of a virus-mimicking nanostructure system for efficient tumor-targeted gene delivery. 1186 Jul 13

We previously reported that supplementation of a cationic liposome with transferrin (Tf) greatly enhanced lipofection efficiency (P.-W. Cheng, Hum. Gene Ther. 1996;7:275-282). In this study, we examined the efficacy of p53 and PTEN tumor suppressor gene therapy in a mouse xenograft model of human prostate PC-3 carcinoma cells, using a vector consisting of dimyristoyloxypropyl-3-dimethylhydroxyethyl ammonium bromide (DMRIE)-cholesterol (DC) and Tf. When the volume of the tumors grown subcutaneously in athymic nude mice reached 50-60 mm(3), three intratumoral injections of the following four formulations were performed during week 1 and then during week 3: (1) saline, (2) DC + Tf + pCMVlacZ, (3) DC + Tf + pCMVPTEN, and (4) DC + Tf + pCMVp53 (standard formulation). There was no significant difference in tumor volume and survival between group 1 and group 2 animals. As compared with group 1 controls, group 3 animals had slower tumor growth during the first 3 weeks but thereafter their tumor growth rate was similar to that of the controls. By day 2 posttreatment, group 4 animals had significantly lower tumor volume relative to initial tumor volume as well as controls at the comparable time point. Also, animals treated with p53 survived longer. Treatment with DC, Tf, pCMVp53, DC + pCMVp53, or Tf + pCMVp53 had no effect on tumor volume or survival. Expression of p53 protein and apoptosis were detected in tumors treated with the standard formulation, thus associating p53 protein expression and apoptosis with efficacy. However, p53 protein was expressed in only a fraction of the tumor cells, suggesting a role for bystander effects in the efficacy of p53 gene therapy. We conclude that intratumoral gene delivery by a nonviral vector consisting of a cationic liposome and Tf can achieve efficacious p53 gene therapy of prostate cancer.
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PMID:p53 and PTEN/MMAC1/TEP1 gene therapy of human prostate PC-3 carcinoma xenograft, using transferrin-facilitated lipofection gene delivery strategy. 1193 74

Elevated body iron stores (serum ferritin >300 microg/L, transferrin saturation TS >50%) are associated with increased risk of liver and lung cancers. To determine whether such association also exists for prostate cancer (PC), we measured serum ferritin, serum iron, total iron-binding capacity (TIBC), and TS in serum samples from 34 men with newly diagnosed, untreated PC and 84 healthy men, ranging in age from 49-78 years. In contrast with other malignancies, men with PC had significantly lower mean concentrations of serum ferritin (156 microg/L) and TS (24.35%) than those without PC (ferritin, 245 microg/L; TS, 31.98%) (p<0.05). The 95% confidence intervals for ferritin were 109-203 microg/L and 205-286 microg/L, and those for TS were 20.29-28.4% and 28.35-35.61% for men with and without PC, respectively. Significant differences were observed between both groups in the distribution of serum ferritin (<100, 101-300, >300 microg/L) and TS (<16, 16-50, >50%) (p<0.05). A lower percentage of cases than of controls had serum ferritin (17.6% versus 29.8%) and TS (5.9% versus 14.7%) above normal. These differences persisted when the analysis was limited to African-American men (31 cases and 52 controls). Data suggest that elevated body iron stores are less common in men with PC compared to those without PC.
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PMID:Serum ferritin levels and transferrin saturation in men with prostate cancer. 1516 Sep 79

Chemotherapy remains the preferred choice of treatment for prostate cancer but modest drug response and significant toxicity by conventional methods of administration limit their efficacy. In our study, we determined the efficacy of paclitaxel (Tx)-loaded biodegradable nanoparticles (NPs) on tumor inhibition. We hypothesized that NPs following conjugation to transferrin (Tf) ligand (NPs-Tf) would enhance the therapeutic efficacy of the encapsulated drug. The antiproliferative activity of NPs was determined in human prostate cancer cell line (PC3) and their effect on tumor inhibition in a murine model of prostate cancer. NPs (approximately 220 nm in diameter, 5.4% w/w drug loading) under in vitro conditions exhibited sustained release of the encapsulated drug (60% release in 60 days). The IC50 (concentration of drug for 50% inhibition of cell growth) of the drug with Tf-conjugated NPs (Tx-NPs-Tf) was about 5-fold lower than that with unconjugated NPs (Tx-NPs) or drug in solution. Animals that received a single-dose intratumoral injection of Tx-NPs-Tf (Tx dose= 4 mg/kg) demonstrated complete tumor regression and greater survival rate than those that received either Tx-NPs or Tx-Cremophor EL formulation. In conclusion, sustained release NPs demonstrated greater antitumor activity following their conjugation to Tf ligand.
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PMID:Efficacy of transferrin-conjugated paclitaxel-loaded nanoparticles in a murine model of prostate cancer. 1535 49

Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer cells and nonprostatic solid tumor neovasculature and is a target for anticancer imaging and therapeutic agents. PSMA acts as a glutamate carboxypeptidase (GCPII) on small molecule substrates, including folate, the anticancer drug methotrexate, and the neuropeptide N-acetyl-l-aspartyl-l-glutamate. Here we present the 3.5-A crystal structure of the PSMA ectodomain, which reveals a homodimer with structural similarity to transferrin receptor, a receptor for iron-loaded transferrin that lacks protease activity. Unlike transferrin receptor, the protease domain of PSMA contains a binuclear zinc site, catalytic residues, and a proposed substrate-binding arginine patch. Elucidation of the PSMA structure combined with docking studies and a proposed catalytic mechanism provides insight into the recognition of inhibitors and the natural substrate N-acetyl-l-aspartyl-l-glutamate. The PSMA structure will facilitate development of chemotherapeutics, cancer-imaging agents, and agents for treatment of neurological disorders.
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PMID:Crystal structure of prostate-specific membrane antigen, a tumor marker and peptidase. 1583 26

Immunodepletion of high-abundance proteins from serum is a widely used initial step in biomarker discovery studies. In the present work we have investigated the reproducibility of the depletion step by comparing 250 serum samples from prostate cancer patients. All samples were depleted on a single immunoaffinity column over a time period of 6 weeks with automated peak detection and fraction collection. Reproducibility in terms of surface area of the depleted serum protein peak at 280nm was below 7% relative standard deviation (R.S.D.) and the collected volume of the relevant fraction was 0.97mL (4.5% R.S.D.). Proteins in the depleted serum fraction were subsequently digested with trypsin and analyzed by MALDI-FT-MS. The degree of the depletion of albumin, transferrin and alpha-1-antitrypsin was determined by comparing the intensity of peptide peaks before and after depletion of 11 samples taken at regular time intervals from amongst the 250 depleted, randomized samples. As a positive control we evaluated peaks of apolipoprotein A1 (the most abundant serum protein remaining after depleteion) showing a clear increase in intensity of these peaks in the depleted samples. From this study we conclude that the depletion of the 250 serum samples was complete and reproducible over a period of 6 weeks.
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PMID:Depletion of high-abundance proteins from serum by immunoaffinity chromatography: a MALDI-FT-MS study. 1704 34

Actinin-4 was originally identified as an actin-binding protein associated with cell motility and cancer invasion and metastasis. However, actinin-4 forms complexes with a large number of different partner proteins and is speculated to have several distinct functions depending on its partner. The level of actinin-4 expression was found to be significantly lower in prostate cancer cells than in non-cancerous basal cells, and restoration of actinin-4 expression inhibited cell proliferation by prostate cancer cell line 22RV1. Immunoprecipitation and mass spectrometry analysis revealed that actinin-4 forms native complexes with several partner proteins in 22RV1 cells, including with beta/gamma-actin, calmodulin, the clathrin heavy chain, non-muscular myosin heavy chain, heterogeneous nuclear ribonucleoprotein A1, and Ras-GTPase-activating protein SH3 domain-binding protein. Clathrin is a coat protein that covers the internalized membrane pit that forms during early endocytosis. We found that other clathrin-related and unrelated cargo proteins, including dynamin, adaptin-delta, beta subunit of neuronal adaptin-like protein, and p47A, also interact with actinin-4. Immunofluorescence microscopy revealed that dynamin and clathrin co-localized with actinin-4 at the sites of membrane ruffling, and transfection of actinin-4 cDNA facilitated the transport of transferrin into perinuclear endosomes. Endocytosis terminates signaling evoked by cell surface receptors and regulates the recycling of receptors and ligands. We identified a panel of proteins whose expression and/or subcellular localization was regulated by actinin-4 by performing organelle fractionation and ICAT-LC-MS/MS. The decreased expression of actinin-4 protein in prostate cancer cells may cause aberrations in the intracellular trafficking of various cell surface molecules and contribute to carcinogenesis.
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PMID:Mass spectrometry analysis of the native protein complex containing actinin-4 in prostate cancer cells. 1715 Oct 21

Urokinase-type plasminogen activator (uPA) on prostate cancer cell surfaces mediates pericellular proteolysis and destruction of extracellular matrix barriers to tumor invasion and metastasis. Increased expression of tumor-associated uPA leads to enhanced tumor dissemination and poor cancer outcomes in men with prostate cancer. Expression of uPA is regulated in part by the oxidant-sensitive transcription factor, NF-kappa B (NF-kappaB), which is activated by intracellular reactive oxygen intermediates (ROI). This study examined the effect of iron on the production of ROI, activation of NF-kappaB and expression of uPA in the human prostate cancer cell line, PC-3. Treatment of PC-3 cells with iron in the form of ferric nitrilotriacetate (FeNTA) in the absence of added transferrin resulted in a dose-dependent increase in cellular ferritin content in both the presence and absence of neutralizing antibody to the transferrin receptor. Cellular uptake of iron resulted in stimulation of intracellular ROI production, and increases in uPA mRNA, antigen, and activity. Concurrent treatment with the iron chelator, desferrioxamine (DFO) abrogated these effects, and treatment with DFO alone inhibited constitutive uPA production. Finally, we observed nuclear translocation, and therefore activation of NF-kappaB in response to iron exposure. We conclude that iron enters PC-3 cells via a non-transferrin dependent pathway and increases uPA expression. Our data indicate that one mechanism by which iron may stimulate uPA production is through the generation of intracellular ROI and activation of NF-kappaB-mediated signaling pathways.
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PMID:Iron stimulates urokinase plasminogen activator expression and activates NF-kappa B in human prostate cancer cells. 1757 74

In vitro invasion and adhesion of stably semaphorin (sema) 3E-transfected PC-3 prostate cancer cells were determined in the presence and absence of transferrin. Invasion and adhesion decreased compared to untransfected cells; however, transferrin reversed the effects. Transferrin differentially regulated E-cadherin and beta-catenin in these cells. Insulin growth factor 3 (IGFBP3) negated the invasive and adhesive effects of transferrin. Transferrin increased binding of insulin growth factor (IGF)-1 to the activated IGF-1 receptor, and IGF-1 mimicked the invasive and adhesive effects of transferrin. These data suggest that transferrin modulates sema3E-transfected cells through an IGFBP3/IGF-1-dependent pathway, in part, by regulation of adhesion proteins.
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PMID:Transferrin reverses the anti-invasive activity of human prostate cancer cells that overexpress sema3E. 1791 56

The objective of this study was to determine whether surface-modified nanoparticles enhance permeability across nasal mucosa, while retaining the effectiveness of the payload. The uptake and permeability of polystyrene nanoparticles (PS-NPs; FluoSpheres) was evaluated across the various regions of the bovine nasal epithelia following conjugation with deslorelin and transferrin. Uptake and transport of PS-NPs, deslorelin-PS-NPs, and transferrin-PS-NPs exhibited regional differences in the order: inferior turbinate posterior (ITP) > medium turbinate posterior (MTP) > medium turbinate anterior (MTA). Uptake and transport also exhibited directionality and temperature dependence in these tissues. Further, uptake as well as transport of functionalized nanoparticles could be inhibited by excess free functionalizing ligand. Confocal microscopy indicated the presence of functionalized nanoparticles in respiratory epithelial cells, as well as other cell types of the nasal tissue. We chose the ITP region for further studies with deslorelin or transferrin-conjugated poly-l-lactide-co-glycolide nanoparticles (PLGA-NPs) encapsulating an anti-VEGF intraceptor (Flt23k) plasmid. Transport of the nanoparticles, as well as the plasmid from the nanoparticles, exhibited the following order: transferrin-PLGA-NPs > deslorelin-PLGA-NPs > PLGA-NPs >> plasmid. The ability of the nanoparticles transported across the nasal tissue to retain the effectiveness of the Flt23k plasmid was evaluated by measuring transfection efficiency (percentage of cells expressing GFP) and VEGF inhibition in LNCaP and PC-3 prostate cancer cells. Transfection efficiencies and VEGF inhibition in LNCaP and PC-3 cells exhibited the following trend: transferrin-PLGA-NPs >or= deslorelin-PLGA-NPs > PLGA-NPs >> plasmid. Further, functionalized nanoparticles exhibited transfection efficiencies and VEGF inhibition significantly superior compared with the routinely used transfecting agent, lipofectamine. Formulating plasmids into nanoparticulate delivery systems enhances the transnasal delivery and gene therapy at remote target cancer cells, which can be further enhanced by nanoparticle functionalization with deslorelin or transferrin.
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PMID:Surface-functionalized nanoparticles for targeted gene delivery across nasal respiratory epithelium. 1960 28


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