Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immunotherapy of cancer, based on eliciting or enhancing the body's own capacity to mount an effective antitumor response, has produced encouraging early results in the areas of melanoma and renal-cell carcinoma. Such treatments utilizing dendritic cells (DC), immune cells that are excellent antigen presenters, are especially promising. We performed a phase I clinical trial assessing the administration of autologous DC pulsed with HLA-A0201-specific prostate-specific membrane antigen (PSMA) for the treatment of 51 men with hormone-refractory prostate cancer. Participants were divided into five groups receiving four or five infusions of peptides alone (PSM-P1 or PSM-P2; group 1 and 2, respectively), autologous DC (group 3), or DC pulsed with PSM-P1 or P2 (group 4 and 5, respectively). No significant toxicity was observed. Immune reactivity against PSM-P2 was detected in HLA-A2+ patients infused with DC pulsed with PSM-P1 or -P2 (group 4 and 5). An average decrease in PSA was observed only in group 5. Seven partial responders were identified based on NPCP criteria + PSA. The excellent tolerance of this treatment approach, as well as the enhanced cellular responses, decreased PSA levels, and partial clinical responses in some patients suggests that it holds great potential in prostate cancer therapy.
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PMID:Dendritic cell-based immunotherapy of prostate cancer. 941 53

The widespread use of prostate-specific antigen (PSA) has revealed that radiation therapy cures adenocarcinoma of the prostate less frequently than previously believed. Biologic factors (such as the complex nature of this disease) and technical factors (geographic miss, inadequate dose to the tumor volume) affect the ability of radiation to effectively treat all patients with prostate cancer. To improve treatment outcome, patients with virulent forms of the disease must be identified. The use of prognostic markers (PSA, prostate-specific membrane antigen, prostate-specific antigen doubling time) and genetic markers (12 lipoxygenase, p53, bcl-2, ploidy) may aid in the development of treatments for these patients. Technical modifications have been made to increase the total dose delivered to the prostate and the accuracy of dose delivery. Brachytherapy, proton therapy and conformal radiation therapy have been used to increase the relative integral dose. Improved prostate targeting may be achieved with the use of fiducial markers, on-line portal imaging, and endorectal magnetic resonance imaging. High linear energy transfer radiation, radiosensitizers and altered fractionation have been used in an attempt to increase the biologic equivalent dose to the tumor. Lastly, hormonal therapy and chemotherapy have been shown to decrease tumor burden and improve local control. All of these methods may improve outcome in patients with adenocarcinoma of the prostate. However, further work must be completed to translate these methods into standards of care.
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PMID:A rational approach to the treatment of prostate cancer with radiation therapy: lessons for the future. 942 69

Understaging is commonly associated with therapeutic failure of surgical intervention in apparently localized prostate cancers. Methods that specifically detect prostate cancer cells in the circulation may be able to identify metastatic cancers and thus aid in the selection of the most adequate therapy. The high sensitivity and specificity of the reverse transcriptase-polymerase chain reaction (RT-PCR) encouraged various groups to investigate the mRNA expression of prostate-specific markers in the peripheral blood of patients with prostate cancer. However, probably due to methodological differences, many contradictory results have been obtained with the markers studied so far: prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSM). For this reason, clinical decisions should not be based yet on RT-PCR results. Future research and long-term follow-up on the patients may point out whether RT-PCR assays, following appropriate standardization, will have an additive value in prostate cancer staging and in prediction of tumor progression.
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PMID:Clinical usefulness of RT-PCR detection of hematogenous prostate cancer spread. 944 45

Prostate cancer is the most common cancer and the second leading cause of cancer-related death among men. New prostatic markers are needed to increase diagnostic and prognostic effectiveness. One such new marker is prostate-specific membrane antigen (PSMA). PSMA is a highly prostate-restricted membrane glycoprotein that is expressed in normal prostatic epithelial cells and elevated in prostate cancers, especially in poorly differentiated, metastatic, and hormone refractory carcinomas. It has been measured in serum with immunocompetitive and Western blot assays, and its levels have been found to be correlated with the prediction of treatment failure and disease prognosis. Reverse transcriptase-polymerase chain reaction (RT-PCR) assays with primers specific for PSMA have been shown to be more effective than PSA-specific primers in detecting hematogenous circulating prostate cancer cells; however, no clear benefit in patient staging or utility as a predictor of clinical outcome or response to treatment has so far been obtained using RT-PCR methods. PSMA is currently utilized as an immunoscintigraphic target using the antibody conjugate CYT-356 (ProstaScint; Cytogen, Princeton, NJ) and has been shown to have clinical value, particularly in detecting occult prostate cancer. Another current application of PSMA is in immunotherapy of prostate cancer, in which promising results have been obtained in a phase I trial, and a phase II trial is underway. The research summarized in this article indicates that PSMA is an excellent target for diagnostic and therapeutic applications in prostate cancer.
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PMID:Prostate-specific membrane antigen: current and future utility. 950 77

Nested reverse transcription (RT)-PCR for prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSM) can detect circulating prostatic cells in patients with prostate cancer. We evaluated the role of a combined screening approach for PSA and PSM in prostate cancer staging. We examined the peripheral blood samples from 136 patients with adenocarcinoma of the prostate (PCA), 15 patients with benign prostatic hyperplasia, 15 normal male subjects, and 5 female subjects. The controls (benign prostatic hyperplasias, normal males, and normal females) were negative for both PSA and PSM. In patients with metastatic PCA (n = 11), 100% were positive by combined PSA/PSM (64% by PSA and 91% by PSM). In biochemical failure PCA patients (n = 18), 39% were positive by PSM, compared to only 6% by PSA. In patients with clinically localized PCA (n = 107), 48% were positive by combined PSA/PSM approach (43% by PSM and 14% by PSA). These results show that PSM is a more sensitive marker than PSA in detecting circulating prostatic cells (P < 0.0001). We correlated preoperative RT-PCR results with final pathological stages in 67 prostatectomy patients. RT-PCR positivity was 81.5% in patients with non-organ-confined disease versus 37.5% in organ-confined disease (P = 0.001). PSA/PSM RT-PCR had an odds ratio of 7.3 (95% confidence interval, 2.3-23.4; P = 0.001) in predicting tumor extracapsular extension. PSA/PSM RT-PCR was a better predictor of tumor extracapsular extension than initial serum PSA, clinical stage, and biopsy Gleason score. Our data show that PSA/PSM nested RT-PCR may provide the staging information unavailable from the current modalities. The ultimate impact of this technique in the management of patients with prostate cancer will require continued investigation.
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PMID:Combined nested RT-PCR assay for prostate-specific antigen and prostate-specific membrane antigen in prostate cancer patients: correlation with pathological stage. 953 48

Although adenocarcinoma of the prostate is recently becoming one of most common malignancies in Japanese men, it still poses many questions regarding its etiology, pathology, pathogenesis and clinical management. Many reports have been made on oncogene and tumor suppressor gene, however, frequent genetic alterations have not been identified during prostate cancer development. Loss of heterozygosity (LOH) on 8p might be an important event in the early stage of prostatic carcinogenesis, whereas alteration in 17p is now considered a late event. Numerous reports about the androgen receptor (AR) gene have revealed that mutations in the coding region of AR possibly results in an acquired resistance to androgen blockade therapy and anti-androgen withdrawal syndrome. It has been also shown that shorter CAG repeats of AR gene are associated with a higher risk of prostate cancer. Regarding molecular diagnosis, prostate-specific membrane antigen (PSM) appears to be a new molecule with many potentially valuable applications. PSM-reverse transcriptase-polymerase chain reaction (RT-PCR) is probably more sensitive and specific than PSA-RT-PCR to predict micrometastatic disease. Gene therapy based on the above molecular aspect is currently under investigation but not generally used yet.
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PMID:[Molecular biological aspect]. 961 16

Jejunal folylpoly-gamma-glutamate carboxypeptidase hydrolyzes dietary folates prior to their intestinal absorption. The complete folylpoly-gamma-glutamate carboxypeptidase cDNA was isolated from a pig jejunal cDNA library using an amplified homologous probe incorporating primer sequences from prostate-specific membrane antigen, a protein capable of folate hydrolysis. The cDNA encodes a 751-amino acid polypeptide homologous to prostate-specific membrane antigen and rat brain N-acetylated alpha-linked acidic dipeptidase. PC3 transfectant membranes exhibited activities of folylpoly-gamma-carboxypeptidase and N-acetylated alpha-linked acidic dipeptidase, while immunoblots using monoclonal antibody to native folylpoly-gamma-glutamate carboxypeptidase identified a glycoprotein at 120 kDa and a polypeptide at 84 kDa. The kinetics of native folylpoly-gamma-carboxypeptidase were expressed in membranes of PC3 cells transfected with either pig folylpoly-gamma-carboxypeptidase or human prostate-specific membrane antigen. Folylpoly-gamma-carboxypeptidase transcripts were identified at 2.8 kilobase pairs in human and pig jejunum, human and rat brain, and human prostate cancer LNCaP cells. Thus, pig folylpoly-gamma-carboxypeptidase, rat N-acetylated alpha-linked acidic dipeptidase, and human prostate-specific membrane antigen appear to represent varied expressions of the same gene in different species and tissues. The discovery of the jejunal folylpoly-gamma-carboxypeptidase gene provides a framework for future studies on relationships among these proteins and on the molecular regulation of intestinal folate absorption.
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PMID:Folylpoly-gamma-glutamate carboxypeptidase from pig jejunum. Molecular characterization and relation to glutamate carboxypeptidase II. 968 95

N-Acetylated alpha-linked acidic dipeptidase (NAALADase) is a neuropeptidase that may modulate glutamatergic neurotransmission. Independent of its characterization in the nervous system, one form of NAALADase was shown to be expressed at high levels in human prostatic adenocarcinomas, and it was designated the prostate-specific membrane antigen (PSMA). The NAALADase/PSMA gene is known to produce multiple mRNA splice forms, and based on previous immunohistochemical evidence, it had been assumed that the human brain and prostate expressed different isoforms of the enzyme. Because PSMA is being actively pursued as a target for autoimmune and cytotoxic targeting strategies to treat prostate cancer, the rigorous comparison of the two forms of the enzyme remained an important but untested question. To assess similarities and/or differences between human brain NAALADase and PSMA, we compared the two molecules using criteria of activity, immunoreactivity and sequences of the corresponding mRNAs. NAALADase from human cerebellar isolates displayed a kinetic profile and pharmacological sensitivities similar to PSMA. Also, Northern hybridization to PSMA cDNA detected indistinguishable sets of 2.8-, 4.0- and 6.0-kb RNA species in human brain and the LNCaP prostatic tumor cell line. In addition, the monoclonal antibody 7E11-C5 directed against the prostatic form of the enzyme immunoprecipitated 82% of human cerebellar NAALADase activity. Moreover, reverse transcription-polymerase chain reaction cloning of cerebellar cDNAs indicated that the human brain and prostate express a common mRNA splice form. Therefore, we conclude that the form of NAALADase also known as PSMA is expressed in brain and comprises a significant fraction of brain NAALADase activity.
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PMID:Molecular characterization of human brain N-acetylated alpha-linked acidic dipeptidase (NAALADase). 969 64

Prostate-specific membrane antigen (PSMA) is a cell surface glycoprotein expressed predominantly by prostate cancer cells. We have characterized four monoclonal antibodies that bind to the extracellular domain of PSMA (Liu et al., Cancer Res., 57: 3629-3634, 1997). Here we report that viable LNCaP cells internalize these antibodies. Laser scanning confocal microscopy reveals that the internalized antibodies accumulate in endosomes, and immunoelectron microscopy reveals that endocytosis of the PSMA-antibody complex occurs via clathrin-coated pits. In addition, a quantitative cell surface biotinylation assay demonstrates that PSMA is constitutively endocytosed in LNCaP cells and that anti-PSMA antibodies increase the rate of internalization of PSMA. These studies suggest that PSMA might function as a receptor mediating the internalization of a putative ligand. The availability of prostate-specific internalizing antibodies should aid the development of novel therapeutic methods to target the delivery of toxins, drugs, or short-range isotopes specifically to the interior of prostate cancer cells.
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PMID:Constitutive and antibody-induced internalization of prostate-specific membrane antigen. 975 9

Although prostate-specific antigen (PSA), or human kallikrein 3, is the most valuable tool available for the diagnosis and management of prostate cancer, as currently used it is insufficiently sensitive and specific for early detection or staging of the malignancy. Many new concepts have been introduced in order to optimize the clinical use of PSA measurements, but each one has its own drawbacks. The molecular forms of PSA, especially the free PSA, seem to be useful for the detection of prostate cancer in men with PSA concentrations falling in the 4-10 microg/l range. New molecular techniques, such as reverse transcriptase polymerase chain reaction for the detection of minimal amounts of PSA messenger RNA and prostate-specific membrane antigen, offer new promise for the prognosis and possibly staging of prostate cancer. On the other hand, human kallikrein 2, a serine protease closely related to PSA that is also expressed predominantly in the prostate, may be a new adjuvant marker for prostate cancer. As for its biological functions, PSA can no longer be regarded as a specific prostate molecule associated mainly with semen liquefaction when it has a possible role as a prognostic indicator in female breast cancer. The biological role of PSA in normal tissues and tumors may be much more complex than previously thought and requires further investigation.
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PMID:Prostate-specific antigen and new related markers for prostate cancer. 980 90


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