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)

A novel monoclonal antibody has been developed that reacts strongly with human prostatic cancer, especially tumors of high grade. This antibody (7E11C-5) is currently in Phase 3 trials as an imaging agent for metastatic disease. We have cloned the gene that encodes the antigen that is recognized by the 7E11C-5 monoclonal antibody and have designated this unique protein prostate-specific membrane (PSM) antigen. PSM antigen is a putative class II transmembranous glycoprotein exhibiting a molecular size of Mr 94,000. Functionally, class II membrane proteins serve as transport or binding proteins or have hydrolytic activity. Preliminary studies have demonstrated binding of pteroylmonoglutamate (folate) to membrane fractions that also cross-reacted with the PSM monoclonal antibody. We observed substantial carboxypeptidase activity as folate hydrolase associated with PSM antigen. The purpose of our study was to demonstrate that human prostatic carcinoma cells expressing PSM antigen exhibit folate hydrolase activity using methotrexate triglutamate (MTXGlu3) and pteroylpentaglutamate (PteGlu5) as substrates. Isolated membrane fractions from four human prostate cancer cell lines (LNCaP, PC-3, TSU-Prl, and Duke-145) were examined for folate hydrolase activity using capillary electrophoresis. After timed incubations at various pH ranges and in the presence and absence of thiol reagents, separation of pteroyl(glutamate)n derivatives was achieved with an electrolyte of sodium borate and SDS, while absorbance was monitored at 300 nm. The results demonstrate clearly that LNCaP cells, which highly express PSM, hydrolyze gamma-glutamyl linkages of MTXGlu3. The membrane-bound enzyme is an exopeptidase, because it progressively liberates glutamates from MTXGlu3 and PteGlu5 with accumulation of MTX and PteGlu1, respectively. The semipurified enzyme has a broad activity from pH 2.5 to 9.5 and exhibits activity maxima at pH 5 and 8. Enzymatic activity is maintained in the presence of reduced glutathione, homocysteine, and p-hydroxymercuribenzoate (0.05-0.5 mm) but was inhibited weakly by DTT (>/=0.2 mm). By contrast to LNCaP cell membranes, membranes isolated from other human prostate adenocarcinoma cells (PC-3, Duke-145, and TSU-Pr1) did not exhibit comparable hydrolase activity, nor did they react with 7E11-C5 monoclonal antibody. After transfection of PC-3 cells with a full-length 2.65-kb PSM cDNA subcloned into a pREP7 eukaryotic expression vector, non-PSM antigen-expressing PC-3 cells developed immunoreactivity to 7E11-C5 monoclonal antibody and demonstrated folate hydrolase activities and optimum pH activity profiles identical to those of LNCaP cells. The membrane-bound enzymes from both LNCaP- and PC-3-transfected cells also have a capacity to hydrolyze an alpha-linked glutamyl moiety from N-acetyl-alpha-aspartylglutamate. We have identified that PSM antigen is a pteroyl poly-gamma-glutamyl carboxypeptidase (folate hydrolase) and is expressed strongly in human prostate cancer. Cancer cells that express this enzyme are resistant to methotrexate therapy. Those developing future therapeutic strategies in the treatment of prostate cancer that utilize folate antagonists need to consider this mechanism of resistance.
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PMID:Prostate-specific membrane antigen: a novel folate hydrolase in human prostatic carcinoma cells. 981 19

Expression of protein kinase C (PKC) isoenzymes -alpha, -beta, -delta, -epsilon, -gamma, -iota, -lambda, -mu, -theta, and -zeta, and of their common receptor for activated C-kinase (RACK)-1, was determined immunohistochemically using specific antibodies in formalin-fixed and paraffin-embedded specimens of early prostatic adenocarcinomas (n = 23) obtained at radical prostatectomy. Expression of each isoenzyme by malignant tissues was compared with nonneoplastic prostate tissues removed at radical cystectomy (n = 10). The most significant findings were decreased PKC-beta expression in early neoplasia when compared to benign epithelium (P < 0.0001), together with a reciprocal increase in expression of PKC-epsilon (P < 0.0001). Detectable levels of PKC-alpha and PKC-zeta were also significantly increased in the cancers (P = 0.045 and P = 0.015 respectively) but did not correlate with either PKC-beta or PKC-epsilon for individual cases. Alterations in the levels of the four PKC isoenzymes occurred specifically and consistently during the genesis and progression of human prostate cancer. PKC-delta, -gamma, and -theta were not expressed in the epithelium of either the benign prostates or the cancers. Levels of expression for PKC-A, -iota, -mu, and RACK-1 were not significantly different between the benign and malignant groups. Although changes in PKC isoenzyme expression may assist in explaining an altered balance between proliferation and apoptosis, it is likely that changes in activity or concentrations of these isoenzymes exert important modulating influences on particular pathways regulating cellular homeostasis. The findings of this study raise an exciting possibility of novel therapeutic intervention to regulate homeostatic mechanisms controlling proliferation and/or apoptosis, including expression of the p170 drug-resistance glycoprotein, intracellular Ca2+ concentrations, and enhanced cellular mobility resulting in the metastatic dissemination of human prostate cancer cells. Attenuation of PKC-beta expression is currently being assessed as a reliable objective adjunct to morphological appearance for the diagnosis of early progressive neoplasia in human prostatic tissues.
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PMID:Protein kinase C isoenzyme patterns characteristically modulated in early prostate cancer. 991 28

The complex carbohydrate molecule globo H hexasaccharide has been synthesized, conjugated to keyhole limpet hemocyanin, and administered with the immunologic adjuvant QS-21 as a vaccine for patients with prostate cancer who have relapsed after primary therapies such as radiation or surgery. Globo H is one of several candidate antigens present on prostate cancer cells that can serve as targets for immune recognition and treatment strategies. The vaccine, given as five subcutaneous vaccinations over 26 weeks, has been shown to be safe and capable of inducing specific high-titer IgM antibodies against globo H. Its immunogenicity was confirmed in prostate cancer patients with a broad range of stages and tumor burdens. Observations of several patients who had evidence of disease relapse restricted to a rising biochemical marker, prostate-specific antigen (PSA), indicated that a treatment effect could occur within 3 months after completion of the vaccine therapy. This effect was manifested as a decline of the slope of the log of PSA concentration vs. time plot after treatment compared with values before treatment. Five patients continue to have stable PSA slope profiles in the absence of any radiographic evidence of disease for more than 2 years. The concept of using PSA slope profiles in assessing early treatment effects in biological therapies such as vaccines awaits further validation in phase II and III trials. The use of a variety of lesser known candidate glycoprotein and carbohydrate antigens in prostate cancer serves as a focus for the development of a multivalent vaccine of the treatment of relapsed prostate cancer in patients with minimal tumor burden.
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PMID:Carbohydrate vaccines in cancer: immunogenicity of a fully synthetic globo H hexasaccharide conjugate in man. 1031 49

An NCI-sponsored, phase II trial of N-(4-hydroxyphenyl)- retinamide (4-HPR) in patients with organ-confined prostate cancer in the period prior to radical prostatectomy was carried out. Thirty-seven men with the histologic diagnosis of prostate cancer planning to have radical prostatectomy entered the study after informed consent and were given 4-HPR (or matching placebo) as a single daily dose (two 100-mg capsules of 4-HPR or two capsules of placebo daily) for 3 weeks prior to surgery. Four men dropped out for unrelated reasons. Thirty-three men completed the study. At the time of surgery, repeat biopsies of the prostate were performed to study the effects of the drug on potential surrogate endpoint biomarkers (SEBs) of malignancy within the tissue. The panel of potential SEBs of malignancy include p53, cytomorphometric indices, ploidy, PNCA, erbB-2, erbB-3, EGF receptor, TGF-alpha tumor-associated glycoprotein-72, fatty acid synthetase and Lewis Y antigen. Twenty-three patients had matching pre- and posttherapy lesions and were considered informative. Results from the patients indicate significant differential expression of biomarkers in pretreatment specimens of uninvolved prostatic tissue (normal-appearing epithelia) prostatic intraepithelial neoplasia (PIN) and prostate cancer. The mean erbB-2 expression was 0.58 in uninvolved vs. 1.04 in PIN (p = 0.002); while the mean erbB-2 expression was 1.35 in prostate cancer (p = 0.0007, uninvolved vs. prostate cancer). A similar pattern of increased biomarker expression between uninvolved and PIN or prostate cancer tissues can be observed for EGF receptor (mean = 1.21, 1.87 and 1.76 for uninvolved, PIN and prostate cancer, respectively) and erbB-3 (mean = 0.81, 1.59 and 1.30 for uninvolved, PIN and prostate cancer, respectively). There were no statistically significant differences in biomarkers observed in the 4-HPR-treated patients when compared with placebo-treated control patients. There was a posttreatment up-regulation of biomarkers observed in both groups of patients. This observation is most likely explained by an effect due to the diagnostic sextant biopsy equally affecting both groups of patients. Results from this study do not demonstrate a chemoprevention effect of 4-HPR on tissue-based SEBs at the dose given.
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PMID:Evaluation of biomarker modulation by fenretinide in prostate cancer patients. 1032 1

In the present study we examined the expression and release of the extracellular matrix glycoprotein fibronectin (FN) in a prostate cancer cell line (LNCaP) and in primary prostatic stromal cells using the reverse transcription-polymerase chain reaction (RT-PCR) and by an enzyme-linked immunosorbent assay. Perturbation experiments in vitro using antibodies directed against FN and the FN receptor were also performed. Immunohistochemistry was used to show the in vivo distribution of FN and the FN receptor in tissue sections of normal human prostate, benign prostatic hyperplasia, and prostate carcinoma. The expression of the oncofetal FN ED-B segment in benign prostatic hyperplasia and prostate carcinoma tissue was investigated by RT-PCR. The FN mRNA was expressed by LNCaP and primary prostatic stromal cells, respectively. Both cell types released FN into the medium in a time-dependent manner, whereby FN secretion was about 2.5-fold higher in cultures of stromal cells relative to LNCaP cells. Blocking FN with anti-FN antibodies resulted in a significant decrease in cell adhesion for LNCaP cells and a change in morphology for the primary stromal cells. FN was located mainly in the stromal compartment of the prostate, showing a distinct distribution pattern in prostate carcinoma, whereas the FN receptor was detectable only in the prostate epithelia. RT-PCR experiments showed the expression of the oncofetal FN ED-B segment in benign prostatic hyperplasia and prostate carcinoma tissue, with a 3.5-fold higher expression in the prostate carcinoma probes. Our data point to an important role for FN in cell adhesion of prostatic cells and show that an alternatively spliced FN mRNA is upregulated in the pathologically altered human prostate.
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PMID:Fibronectin in human prostatic cells in vivo and in vitro: expression, distribution, and pathological significance. 1046 12

Human prostate cancer has the propensity to metastasize to the bone where reciprocal cellular interactions between prostate cancer and bone cells are known to occur. Osteopontin (OPN), a noncollagenous bone extracellular matrix, is a secreted adhesive glycoprotein with a functional RGD cell-binding domain that interacts with the alpha(v)beta3 cell surface integrin heterodimer. OPN has been associated with malignant transformation as well as being ligand to the CD44 receptor. Polyclonal antibodies to human OPN (hOPN) were prepared, and specificity was shown by preabsorption with recombinant hOPN. The stimulatory effect of hOPN protein and the inhibitory effect of hOPN antibody on human prostate cancer cell lines LNCaP and C4-2 were assessed by induction or inhibition of anchorage-independent growth, respectively. Expression of hOPN mRNA in prostate cancer cell lines and human prostate cancer tissue specimens were measured by mRNA blot analysis. Protein expression was assessed by immunohistochemistry in human prostate cancer specimens and by Western blot analysis in prostate cancer cell lines. hOPN stimulated anchorage-independent growth of the human prostate cancer cell lines LNCaP and C4-2 in vitro. Antibodies to hOPN inhibited the growth-stimulatory effect by endogenous OPN, which can be overcome by the addition of exogenous hOPN. hOPN mRNA and protein are expressed in human prostate cancer cell lines in vitro and in clinical human prostate cancer specimens. These findings taken together suggest that OPN may act as a paracrine and autocrine mediator of prostate cancer growth and progression.
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PMID:Osteopontin: possible role in prostate cancer progression. 1047 15

Measurement of serum levels of the prostate specific antigen (PSA) is now widely used for the diagnosis of prostate cancer and benign prostate hyperplasia. This serum marker is of value since it is derived only from the tissue of interest, but increased levels of PSA in serum do not allow a completely clear cut diagnosis of benign versus malignant changes. Since PSA is a glycoprotein with one asparagine linked oligosaccharide, and since malignant transformation often leads to an increased branching of such oligosaccharides, we initially studied the asparagine linked structures on PSA made by a cell line derived from malignant metastatic prostate tissue. We observed that unlike normal PSA, which bears only biantennary oligosaccharides, PSA from the metastatic cell line has a mixture of biantennary and triantennary oligosaccharides. Further experiments will reveal carbohydrate differences derived from the PSA from sera or, prostate tissue of normal versus prostate cancer patients, and of the utility of such carbo-hydrate differences as a possible diagnostic marker for prostate cancer.
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PMID:Glycotyping of prostate specific antigen. 1064 8

The urokinase-type plasminogen activator receptor (uPAR) exists as a GPI anchored glycoprotein (Mr=50-60 kDa) on the surface of various cell types. This receptor can be bound by or cleaved by urokinase. The cleaved receptor, soluble urokinase-type plasminogen activator receptor (suPAR), with an Mr=35 kDa has no known physiological function and can be identified circulating in the blood of normal individuals. Although no function has been characterized, the soluble receptor has been reported to be of clinical significance. The objective of this study is to characterize novel serum markers that can be used for the early detection of prostate cancer and to predict patient prognosis. Thirty-nine patients at the University of Yaounde I, Yaounde, Cameroon, West Africa were examined for prostatic disorders. Of these, 46% were diagnosed with benign prostate hyperplasia (BPH), while 44% of the patients were diagnosed via biopsy with prostate cancer and graded accordingly. Here we show that serum from patients with BPH or prostate cancer contains elevated levels of suPAR. To examine the significance of suPAR as a diagnostic factor, we used a suPAR ELISA kit and compared these results with serum levels of prostate specific antigen (PSA), the current diagnostic marker for prostate cancer. PSA and serum suPAR levels in BPH and cancer patients were greatly elevated in the majority of patients, while others had undetectable levels of either. Serum levels of suPAR were high in cancer patients as well as, although to a lesser degree, in patients with BPH. Cancer patients who died during the follow-up period were found to have consistently higher serum suPAR levels than correlating serum PSA levels. These preliminary findings are the first evaluating serum suPAR levels as a possible diagnostic marker for the early detection of prostate cancer and for the prediction of patient prognosis.
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PMID:Expression of soluble urokinase plasminogen activator receptor may be related to outcome in prostate cancer patients. 1085 62

Prostate specific antigen (PSA) is a glycoprotein found in the epithelial cells of the prostatic duct and acini. PSA is elevated in all four stages of prostate cancer as well as in benign prostatic hypertrophy. We evaluated a new chemiluminescent assay for PSA by comparing this assay with the microparticle enzyme immunoassay for PSA (MEIA) on the AxSYM analyzer (Abbott Laboratories, Abbott Park, IL) and a Hybritech Tandem R assay for PSA. The new chemiluminescent assay is recently available from Bayer Diagnostics (Tarrytown, NY) and can be run using the ACS: 180 Plus analyzer. Precision of the new chemiluminescent assay was evaluated using commercially available controls (Bayer Diagnostics). The within-run and total CVs were 6.4 and 8.7% for the low control (mean: 0.43 microg/L), 1.6 and 5.2% for the next level control (mean:1.94 mg/L), 4.3 and 4.9% for the medium control (mean: 2.10 mg/L), 1.2 and 3.9% for the high control 1 (mean: 11.52 mg/L), and finally 3.2 and 6.9% for the high control 2 (mean: 21.52 mg/L). The spike recovery varied from 94.2 to 109.6% for five different specimens we studied. We also observed excellent dilution recoveries. For example, in the specimen supplemented with 3.02 mg/L of PSA, the dilution recoveries were 102. 1, 104.7, and 103.7% for 1:2, 1:4, and 1:8 dilutions, respectively. We analyzed 113 serum specimens from patients with various concentrations of PSA (range 0.5 mg/L-2040 mg/L) using the new chemiluminescent assay and compared our results with the MEIA and Hybridtech (Tandem-R PSA) assays. Using x axis as the PSA concentrations obtained by the Tandem-R assay and the y axis as the PSA values obtained by the new chemiluminescent assay, we observed the following regression equations: y = 1.04 x -0.19 (r = 0.99, n = 112). One specimen with PSA concentrations of 2040 microg/L by the MEIA and 2156 microg/L by the chemiluminescent assay was not used for regression analysis. Similarly using x axis as the PSA concentrations obtained by the MEIA assay and y axis as the PSA concentrations obtained by the chemiluminescent assay, we observed the following regression equation: y = 0.88 + 0.02 (r = 0.99, n = 112). We conclude that the new chemiluminescent assay has excellent precision and the results compared well with the existing assays.
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PMID:Performance evaluation of a new chemiluminescent assay for prostate specific antigen. 1090 69

Prostate-specific antigen is a serine protease that is a member of the kallikrein family. It is widely used as an indicator of tumor burden and as a surrogate marker for disease progression in men with androgen-independent prostate cancer. It has been shown that the expression and/or secretion of this glycoprotein can be regulated by pharmacological agents. The effects of these agents on PSA may be independent of their effects on cell growth. For example, a pharmacological agent may down-regulate PSA expression/secretion but have no effect on tumor cell growth. In this case, a patient receiving this therapeutic agent might be falsely considered as having a clinical response. Alternatively, an agent might up-regulate PSA expression/secretion and have an inhibitory effect on cell growth. A patient receiving this therapeutic agent might be diagnosed with progressive disease unless an alternative method for assessing tumor burden is used. Thus, when an agent is to be evaluated in a clinical trial utilizing PSA as a marker for disease progression, it is important to prospectively test whether the agent has an effect on PSA expression and/or secretion. In addition, it is equally important to understand how these regulatory effects relate to cell growth. The purpose of this review is to describe several agents that have been tested for their regulatory effects on PSA and to discuss potential mechanisms of by which this regulation may occur. The implications of these findings in the evaluation of new agents in androgen-independent prostate cancer will be considered.
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PMID:The control of prostate-specific antigen expression and gene regulation by pharmacological agents. 1117 39


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