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Molecular Imaging of Viable Cancer Cells
Published in Shoogo Ueno, Bioimaging, 2020
In order to expand the range of target cancers, we next focused on cancer-associated carboxypeptidases. Especially, we focused on the glutamate carboxypeptidase activity of prostate-specific membrane antigen (PSMA), which is a type II transmembrane glycoprotein that is overexpressed in prostate cancer.53–55 Based on our finding that aryl glutamate conjugates with an azoformyl linker are recognized by PSMA and have a sufficiently low LUMO energy level to quench the fluorophore through photoinduced electron transfer, we established a new design strategy for activatable fluorescence probes to visualize carboxypeptidase activity, and developed a first-in-class activatable fluorescence probe for detecting the carboxypeptidase activity of PSMA (Figure 2.11).56 We confirmed that the developed probe allowed us to visualize the CP activity of PSMA in living cells and in clinical specimens from prostate cancer patients. This probe is expected to be useful for rapid intraoperative detection and diagnosis of prostate cancer.
Radiopharmaceuticals for SPECT
Published in Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman, Molecular Imaging in Oncology, 2008
Prostate-specific membrane antigen (PSMA) is an integral membrane protein with an enzymatic active site in an extracellular domain. PSMA is upregulated in prostate cancer, particularly in advanced, hormone-independent and metastatic disease (239). It is also expressed in the neovasculature of nearly all solid tumors (240). Adding further to the attractiveness of PSMA as an imaging target is its limited pattern of expression, primarily within prostate, small bowel, proximal renal tubule and brain (241). Within the brain PSMA is known as glutamate carboxypeptidase II (GCPII, also known as NAAG peptidase), where it catalyzes the hydrolysis of NAAG to glutamate and N-acetylaspartate (242). PSMA/GCPII is an active target for the development of imaging agents and has recently been reviewed (243). One class of PSMA inhibitors has been designed by replacing the glutamide moiety of a PSMA substrate-like NAAG with a urea. Two urea based PSMA inhibitors DCIT and compound 28 labeled with single photon emitters that have shown high specific uptake in PSMA + mouse tumor xenografts are shown in Figure 18 (244,245).
Oxidative Injury in Diabetic Neuropathy
Published in Emmanuel Opara, NUTRITION and DIABETES, 2005
James W. Russell, Alexander J. Kaminsky
There is increasing evidence that the metabotropic glutamate receptors (mGluRs) modulate cellular injury (98–100), although the role of the mGluRs in diabetic neuropathy is presently unknown. The mGluRs are a subfamily of glutamate receptors that are G-protein coupled and linked to second-messenger systems (100, 101). In addition to strong mechanism-driven evidence that GCPII inhibitors and mGluR3 agonists are neuroprotective, there is preclinical data that GCPII inhibitors ameliorate diabetic neuropathy in animal models (102). GCPII inhibition has beneficial effects on hyperalgesia, nerve function, and structural degenerative changes in diabetic neuropathy. The Glutamate carboxypeptidase II (GCP II) inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) is protective against glucose-induced programmed cell death (PCD) and neurite degeneration in DRG neurons in a cell-culture model of diabetic neuropathy (103). In this model, inhibition of neuronal PCD is mediated by the Group II metabotropic glutamate receptor, mGluR3. 2-PMPA neuroprotection is completely reversed by the mGluR3 antagonist, (S)-α-ethylglutamic acid (EGLU), but not by Group I and III mGluR inhibitors. Other mGluR3 agonists, for example, (2R, 4R)-4-aminopyrrolidine-2, 4-dicarboxylate (APDC), and N-acetyl-aspartyl-glutamate (NAAG), provide protection to neurons exposed to high glucose conditions, consistent with the concept that 2-PMPA neuroprotection is mediated by increased NAAG activity. Furthermore, the direct mGluR3 agonist, APDC, prevents induction of ROS (104). Together, these findings are consistent with an emerging concept that mGluRs may protect against cellular injury by regulating oxidative stress in the neuron and may represent a novel mechanism to prevent oxidative injury in diabetic neuropathy.
Prostate-specific membrane antigen-directed imaging and radioguided surgery with single-photon emission computed tomography: state of the art and future outlook
Published in Expert Review of Medical Devices, 2022
Luca Filippi, Barbara Palumbo, Viviana Frantellizzi, Susanna Nuvoli, Giuseppe De Vincentis, Angela Spanu, Orazio Schillaci
PSMA is a zinc-containing metal-enzyme transmembrane glycoprotein of type II, that is intensely up-regulated in PC cells with a grade of expression strictly correlated with tumor stage and biological aggressiveness. PSMA’s exact role in prostate normal tissue is still unclear, although it has been hypothesized it might have a trophic function. In past years 111In-capromab pendetide, a monoclonal antibody targeting PSMA, was used for the imaging of PC recurrence and metastases, but it showed limited sensitivity and specificity [32], since this radiocompound recognizes the PSMA-intracytoplasmatic domain that is available only in necrotic or dying tumor cells. Worthy of note, glutamate carboxypeptidase activity is localized in PSMA extracellular domain, thus being exposed to the extracellular space and particularly suitable for theranostic approaches [33].
The potential of PSMA-targeted alpha therapy in the management of prostate cancer
Published in Expert Review of Anticancer Therapy, 2020
Luca Filippi, Agostino Chiaravalloti, Orazio Schillaci, Oreste Bagni
The identification of PSMA as a suitable theranostic target dates back to the 80s when prostate cancer cell lines were developed and a monoclonal antibody (7E11 MoAb) was produced toward the membrane of these cells. PSMA, which is overexpressed in PCa, is a type II transmembrane protein, codified by a gene located in the chromosome 11, characterized by 3 constitutive structures: a 19-amino-acid internal portion, a 24-amino-acid transmembrane portion, and a 707-amino-acid external portion [22]. PSMA presents enzymatic activity as a glutamate-carboxypeptidase, whose function in normal prostate and in other sites of expression has still to be fully understood. Figure 1 schematically represents the structures of PSMA with its target sites for the different molecular probes applied in theranostics.
Prostate cancer proteomics: clinically useful protein biomarkers and future perspectives
Published in Expert Review of Proteomics, 2018
Paula Intasqui, Ricardo P. Bertolla, Marcus Vinicius Sadi
To identify biomarkers of disease progression, the proteomes from tumors Gleason ≥7 (4 + 3) and ≤7 (3 + 4) were compared. The authors identified nuclear receptor coactivator 7 (NCOA7), glutamate carboxypeptidase 2 (FOLH1), and pro-neuropeptide Y (NPY) as positive biomarkers for cancer (increased in cancer). NPY was positively stained in immunohistochemistry only in prostate cancer, but not in other cancer types, such as lung and liver cancers. A moderate or strong expression was observed in 40% of prostate cancer, which also presented a significantly increased risk of prostate-cancer related death, especially in cases scored as Gleason ≤7 [7].