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)

Limited options for the treatment of prostate cancer have spurred the search for new therapies. One innovative approach is the use of targeted alpha therapy (TAT) to inhibit cancer growth, using an alpha particle emitting radioisotope such as (213)Bi. Because of its short range and high linear energy transfer (LET), alpha-particles may be particularly effective in the treatment of cancer, especially in inhibiting the development of metastatic tumors from micro-metastases. Prostate-specific membrane antigen (PSMA) is expressed in prostate cancer cells and the neovasculature of a wide variety of malignant neoplasms including lung, colon, breast and others, but not in normal vascular endothelium. The expression is further increased in higher-grade cancers, metastatic disease and hormone-refractory prostate cancer (PCA). J591 is one of several monoclonal antibodies (mabs) to the extracellular domain of PSMA. Chelation of J591 mab with (213)Bi forms the alpha-radioimmunoconjugate (AIC). The objective of this preclinical study was to design an injectable AIC to treat human prostate tumors growing subcutaneously in mice. The anti-proliferative effects of AIC against prostate cancer were tested in vitro using the MTS assay and in vivo with the nude mice model. Apoptosis was documented using terminal deoxynucleotidyl transferase [TdT]-mediated deoxyuridinetriphosphate [dUTP] nick end-labeling (TUNEL) assay, while proliferative index was assessed using the Ki-67 marker. We show that a very high density of PSMA is expressed in an androgen-dependent human PCA cell line (LNCaP-LN3) and in tumor xenografts from nude mice. We also demonstrate that the AIC extensively inhibits the growth of LN3 cells in vitro in a concentration-dependent fashion, causing the cells to undergo apoptosis. Our in vivo studies showed that a local AIC injection of 50 microCi at 2 days post-cell inoculation gave complete inhibition of tumor growth, whereas results for a non-specific AIC were similar to those for untreated mice. Further, after 1 and 3 weeks post-tumor appearance, a single (100 microCi/100 microl) intra-lesional injection of AIC can inhibit the growth of LN3 tumor xenografts (volume<100 mm(3)) in nude mice. Tumors treated with AIC decreased in volume from a mean 46+/-14 mm(3) in the first week or 71+/-15 mm(3) in the third week to non-palpable, while in control mice treated with a non-specific AIC using the same dose, tumor volume increased from 42 to 590 mm(3). There were no observed side effects of the treatment. Because of its in vitro cytotoxicity and these anti-proliferative properties in vivo, the (213)Bi-J591 conjugate has considerable potential as a new therapeutic agent for the treatment of prostate cancer.
Prostate Cancer Prostatic Dis 2002
PMID:In vitro and preclinical targeted alpha therapy of human prostate cancer with Bi-213 labeled J591 antibody against the prostate specific membrane antigen. 1519 29

Human glutamate carboxypeptidase II (GCPII) is a co-catalytic metallopeptidase and its putative catalytic domain is homologous to the aminopeptidases from Vibrio proteolyticus and Streptomyces griseus. In humans, the enzyme is expressed predominantly in the nervous system and the prostate. The prostate form, termed prostate-specific membrane antigen, is overexpressed in prostate cancer and is used as a diagnostic marker of the disease. Inhibition of the form of GCPII expressed in the central nervous system has been shown to protect against ischemic injury in experimental animal models. Human GCPII consists of 750 amino acids, and six individual domains were predicted to constitute the protein structure. Here, we report the analysis of the contribution of these putative domains to the structure/function of recombinant human GCPII. We cloned 13 mutants of human GCPII that are truncated or extended at one or both the N- and C-termini of the GCPII sequence. The clones were used to generate stably transfected Drosophila Schneider's cells, and the expression and carboxypeptidase activities of the individual protein products were determined. The extreme C-terminal region of human GCPII was found to be critical for the hydrolytic activity of the enzyme. The deletion of as few as 15 amino acids from the C-terminus was shown to completely abolish the enzymatic activity of GCPII. Furthermore, the GCPII carboxypeptidase activity was abrogated upon removal of more than 60 amino acid residues from the N-terminus of the protein. Overall, these results clearly show that amino acid segments at the N- and C-termini of the ectodomain of GCPII are essential for its carboxypeptidase activity and/or proper folding.
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PMID:Amino acids at the N- and C-termini of human glutamate carboxypeptidase II are required for enzymatic activity and proper folding. 1520 43

Carcinoma of the prostate is the second leading cause of male cancer-related death in the United States. Better indicators of prostate cancer presence and progression are needed to avoid unnecessary treatment, predict disease course, and develop more effective therapy. Numerous molecular markers have been described in human serum, urine, seminal fluid, and histological specimens that exhibit varying capacities to detect prostate cancer and predict disease course. However, to date, few of these markers have been adequately validated for clinical use. The purpose of this review is to examine the current status of these markers in prostate cancer and to assess the diagnostic potential for future markers from identified genes and molecules that display loss, mutation, or alteration in expression between tumor and normal prostate tissues. In this review we cite 91 molecular markers that display some level of correlation with prostate cancer presence, disease progression, cancer recurrence, prediction of response to therapy, and/or disease-free survival. We suggest criteria to consider when selecting a marker for further development as a clinical tool and discuss five examples of markers (chromogranin A, glutathione S-transferase pi 1, prostate stem cell antigen, prostate-specific membrane antigen, and telomerase reverse transcriptase) that fulfill some of these criteria. Finally, we discuss how to conduct evaluations of candidate prostate cancer markers and some of the issues involved in the validation process.
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PMID:Detection of prostate cancer and predicting progression: current and future diagnostic markers. 1521 24

ProstaScint (CYT-356 or capromab pendetide, Cytogen) is an 111In-labeled monoclonal mouse antibody specific for prostate-specific membrane antigen, a prostate transmembrane glycoprotein that is upregulated in prostate adenocarcinoma. ProstaScint scans are US Food and Drug Administration approved for pretreatment evaluation of metastatic disease in high-risk patients. They are also approved for post-prostatectomy assessment of recurrent disease in patients with a rising prostate-specific antigen level. This review explores the literature on ProstaScint and its use in guiding the treatment of prostate cancer. A novel technique for identifying areas of cancer within the prostate using ProstaScint images fused with pelvic computed tomography scans is also described. The identification of areas of high antibody signal provides targets for radiotherapeutic dose escalation, with the overall goals of improving treatment outcome while preserving adjacent tissue structures and decreasing treatment morbidity.
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PMID:Role of ProstaScint for brachytherapy in localized prostate adenocarcinoma. 1522 91

Efforts are increasing to identify and evaluate diagnostic and therapeutic markers for prostate cancer patients. One of these, prostate-specific membrane antigen (PSMA), a transmembrane protein highly expressed in all types of prostatic tissue (eg, benign epithelium, benign prostatic hyperplasia, prostatic intra-epithelial neoplasia and adenocarcinomas, with increased binding affinity for malignant cells), is becoming an increasingly important diagnostic and therapeutic marker, not only for prostate cancer, but possibly for other malignant lesions. Recent studies have demonstrated PSMA expression in endothelial cells of tumor-associated neovasculature (including carcinoma of the colon, breast, bladder, pancreas, kidney and melanoma), thus greatly expanding its possible beneficial role, especially as new anti-PSMA mAbs continue to be developed and refined. Future diagnostic and therapeutic interventions utilizing these antibodies will become increasingly important in not only prostate cancer but perhaps many other different malignancy types.
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PMID:Monoclonal antibodies and prostate-specific membrane antigen. 1524 49

Prostate-specific antigen (PSA) has long been criticized for its lack of specificity in screening for the occurrence of prostate cancer. In this study, we tried to measure levels of another biomarker, prostate-specific membrane antigen (PSM), in the peripheral circulation from subjects with either prostate cancer or benign prostatic hyperplasia (BPH). Total RNA was extracted from blood samples of 70 patients with prostate cancer and 19 with BPH. Reverse transcription was performed to convert mRNA to cDNA. The cDNA was analyzed with a novel real-time quantitative polymerase chain reaction (PCR) protocol to measure PSM mRNA levels in the circulation. Melting curve analysis was adapted to assure that correct amplification data were obtained. Results showed that 41 of 70 prostate cancer patients had positive results, whereas 9 of 19 BPH cases were negative. Therefore, the sensitivity and specificity were determined to be 58.6% and 47.4%, respectively. For comparison, traditional nested PCR was performed to investigate whether the new method was superior. The sensitivity and specificity of nested PCR were determined to be 27.1% and 57.9%, respectively. The detection limits of these two methods were 0.0005 ng (for the real-time quantitative PCR method) and 0.5 ng of PSM-cDNA (for the nested PCR method). In conclusion, we have successfully developed a novel, noninvasive real-time quantitative PCR method to detect the PSM mRNA levels in the peripheral circulation of prostate cancer subjects. This method may provide references for urologists diagnosing prostate cancer or monitoring the patient's condition after treatment.
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PMID:The use of real-time quantitative PCR to detect circulating prostate-specific membrane antigen mRNA in patients with prostate carcinoma. 1525 56

In order to reconfirm their diagnostic and predictive significance, bio- and molecular-markers of urological cancers (prostate, urothelial, kidney, and testicular cancer) are reviewed. In prostate cancer, although prostatic specific antigen (PSA) is a gold standard marker for its screening and monitoring, recent studies have revealed that PSA-related markers have additional information for patients with a gray zone PSA score. Prostate-specific membrane antigen (PSMA) may provide new applications for detection of high-grade cancer or microscopic circulating prostate cancer cells in the blood. In urothelial cancers, several urinary markers are available and may be helpful in the diagnosis of lower-grade urothelial cancers, which have a low sensitivity of urinary cytology. In testicular cancer, lactate dehydrogenase (LDH), alpha-fetoprotein (AFP), and human chorionic gonadotropin (hCG) are essential markers not only to determine the tumor stage but also the prognosis of the patient. In renal cell carcinoma (RCC), unfortunately, no definitive biomarker is available for its diagnosis and monitoring. Thus, we must find new specific bio- and molecular-markers that reflect the biological activity of RCC.
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PMID:[Significance of current bio- and molecular-markers in urological cancers]. 1527 77

Prostate-related antigens, including prostate-specific membrane antigen (PSMA) and prostatic acid phosphatase (PAP), can be targets in specific immunotherapy for prostate cancer. In this study, we attempted to newly identify epitope peptides from these 2 antigens, which are immunogenic in human histocompatibility leukocyte antigen (HLA)-A2+ prostate cancer patients. Twenty-nine peptides (PSMA with 15 and PAP with 14) were prepared based on the HLA-A2 binding motif. Based on our previous finding that antigenic peptides recognized by both cellular and humoral immune systems are useful for peptide-based immunotherapy, 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, PSMA441-450 and PAP112-120 peptides were found to be frequently recognized by IgG in plasma from prostate cancer patients. These 2 candidates effectively induced HLA-A2-restricted and prostate cancer-reactive CTLs in HLA-A2+ prostate cancer patients with several HLA-A2 subtypes. In addition, their cytotoxicity was mainly dependent on peptide-specific and CD8+ T cells. These results indicate that these PSMA441-450 and PAP112-120 peptides could be promising candidates for peptide-based immunotherapy for HLA-A2(+) prostate cancer.
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PMID:Prostate-related antigen-derived new peptides having the capacity of inducing prostate cancer-reactive CTLs in HLA-A2+ prostate cancer patients. 1528 44

Extracellular nucleic acids could serve as molecular markers in the early detection of cancer and in the prediction of disease outcome. In this study we examined six molecular markers, such as: variations in the quantity of DNA in plasma, glutathione-S-transferase P1 (GSTP1) gene methylation status in plasma, carcinoembryonic antigen (CEA) and prostate-specific membrane antigen (PSMA) mRNA in peripheral blood mononuclear cells (PBMC), and plasma samples from prostate cancer patients in different stages. The combination of DNA load and GSTP1 promoter methylation status identified 83% (10/12) of the prostate cancer patients before therapy. This study shows that free circulating DNA can be detected in patients with prostate cancer compared with disease-free individuals, and suggests a new, noninvasive approach for early detection of prostate cancer.
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PMID:Cell-free DNA and RNA in plasma as a new molecular marker for prostate cancer. 1549 Sep 75

Nucleic acid ligands (aptamers) are potentially well suited for the therapeutic targeting of drug encapsulated controlled release polymer particles in a cell- or tissue-specific manner. We synthesized a bioconjugate composed of controlled release polymer nanoparticles and aptamers and examined its efficacy for targeted delivery to prostate cancer cells. Specifically, we synthesized poly(lactic acid)-block-polyethylene glycol (PEG) copolymer with a terminal carboxylic acid functional group (PLA-PEG-COOH), and encapsulated rhodamine-labeled dextran (as a model drug) within PLA-PEG-COOH nanoparticles. These nanoparticles have the following desirable characteristics: (a) negative surface charge (-50 +/- 3 mV, mean +/- SD, n = 3), which may minimize nonspecific interaction with the negatively charged nucleic acid aptamers; (b) carboxylic acid groups on the particle surface for potential modification and covalent conjugation to amine-modified aptamers; and (c) presence of PEG on particle surface, which enhances circulating half-life while contributing to decreased uptake in nontargeted cells. Next, we generated nanoparticle-aptamer bioconjugates with RNA aptamers that bind to the prostate-specific membrane antigen, a well-known prostate cancer tumor marker that is overexpressed on prostate acinar epithelial cells. We demonstrated that these bioconjugates can efficiently target and get taken up by the prostate LNCaP epithelial cells, which express the prostate-specific membrane antigen protein (77-fold increase in binding versus control, n = 150 cells per group). In contrast to LNCaP cells, the uptake of these particles is not enhanced in cells that do not express the prostate-specific membrane antigen protein. To our knowledge, this represents the first report of targeted drug delivery with nanoparticle-aptamer bioconjugates.
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PMID:Nanoparticle-aptamer bioconjugates: a new approach for targeting prostate cancer cells. 1552 Jan 66


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