Asunto(s)
Antígenos de Superficie , Glutamato Carboxipeptidasa II , Glándulas Salivales , Humanos , Ligandos , RadiofármacosRESUMEN
In this review, we cover the evolution of knowledge on the biology of prostate-specific membrane antigen (PSMA) and its translation to therapy. The usual key to discovery is a realistic model for experimentation and for testing a hypothesis. A realistic model is especially needed in the case of the human prostate, which differs significantly from the prostate of species often used as research models. We will emphasize the genetic characterization of PSMA, the nature of the PSMA protein, and its role as a carboxypeptidase, with differing important substrates and products in different tissues. We give special prominence to the importance of PSMA as a target for imaging and therapy in prostate cancer and its underdeveloped role for imaging and targeting the neovasculature of tumors other than prostate cancer. Lastly, we bring attention to its importance in other nonprostatic tissues.
Asunto(s)
Diagnóstico por Imagen/métodos , Glutamato Carboxipeptidasa II/metabolismo , Radioterapia/métodos , Ácido Fólico/metabolismo , Humanos , Masculino , Terapia Molecular Dirigida , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismoRESUMEN
Prostate Specific Membrane Antigen (PSMA) is strongly expressed in prostate cancer. Recently a number of low-molecular-weight inhibitors have demonstrated excellent PSMA targeting activity for both imaging as well as Lutecium-177 radiotherapy in human trials. The paper by Choy et al raises the question of whether we can further increase the effectiveness of PSMA targeted therapy by adding an albumin-binding entity to low-molecular-weight agents.
Asunto(s)
Glutamato Carboxipeptidasa II , Neoplasias de la Próstata , Albúminas , Amidas , Animales , Antígenos de Superficie , Humanos , Ligandos , Masculino , Ratones , Peso Molecular , Ácidos Fosfóricos , Distribución TisularRESUMEN
Prostate cancer is the most common noncutaneous malignancy affecting men in North America. Radical prostatectomy remains a definitive treatment for prostate cancer. However, prostate surgeries are still performed "blindly" with the extent of tumor infiltration past the margins of the surgery only being determined postoperatively. An imaging modality that can be used during surgery is needed to help define the tumor margins. With its abundant expression in prostate cancer, prostate-specific membrane antigen (PSMA) is an ideal target for detection of prostate cancer. The purpose of this study was to develop PSMA-targeted near-infrared (NIR) optical imaging probes for intraoperative visualization of prostate cancer. We synthesized a high-affinity PSMA ligand (PSMA-1) with low molecular weight and further labeled it with commercially available NIR dyes IRDy800 and Cy5.5. PSMA-1 and PSMA-1-NIR conjugates had binding affinities better than the parent ligand Cys-CO-Glu. Selective binding was measured for each of the probes in both in vitro and in vivo studies using competitive binding and uptake studies. Interestingly, the results indicated that the pharmacokinetics of the probes was dependent of the fluorophore conjugated to the PSMA-1 ligand and varied widely. These data suggest that PSMA-targeted probes have the potential to be further developed as contrast agents for clinical intraoperative fluorescence-guided surgery.
Asunto(s)
Colorantes Fluorescentes/química , Neoplasias de la Próstata/diagnóstico , Espectroscopía Infrarroja Corta/métodos , Animales , Antígenos de Superficie/química , Línea Celular Tumoral , Medios de Contraste/química , Glutamato Carboxipeptidasa II/química , Humanos , Masculino , Ratones , Ratones Desnudos , Neoplasias de la Próstata/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Prostate-specific membrane antigen (PSMA) is an ideal biomarker for prostate cancer. A previously reported 2-5A conjugate RBI1033 (3) showed binding affinity more than 10 times higher than the parent urea-based compound (S)-2-(3-((S)-5-amino-1-carboxypentyl)ureido) pentanedioic acid (1). The purpose of this work is to further optimize the structure of 3 to identify highly selective ligands of PSMA. It was found that conjugates having 2-5A in their structure showed extraordinary improved binding affinity to PSMA compared with compound 1. Removal of 2-5A significantly reduced its biological activity. The results will provide a path to agents for targeted imaging and treatment of prostate cancer.
Asunto(s)
Nucleótidos de Adenina/química , Nucleótidos de Adenina/farmacología , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Oligorribonucleótidos/química , Oligorribonucleótidos/farmacología , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Nucleótidos de Adenina/metabolismo , Antígenos de Superficie , Unión Competitiva , Transporte Biológico , Línea Celular Tumoral , Humanos , Ligandos , Masculino , Imagen Molecular , Metástasis de la Neoplasia , Oligorribonucleótidos/metabolismo , Neoplasias de la Próstata/patología , Inhibidores de Proteasas/metabolismo , Relación Estructura-ActividadRESUMEN
Prostate specific membrane antigen (PSMA) is overexpressed in prostatic adenocarcinoma (CaP), and its expression is negatively regulated by androgen stimulation. However, it is still unclear which factors are involved in this downregulation. TMPRSS2-ERG fusion is the most common known gene rearrangement in prostate carcinoma. Androgen stimulation can increase expression of the TMPRSS2-ERG fusion in fusion positive prostate cancer cells. The purpose of this investigation is to determine whether PSMA expression can be regulated by the TMPRSS2-ERG gene fusion. We employed two PSMA positive cell lines: VCaP cells, which harbor TMPRSS2-ERG fusion, and LNCaP cells, which lack the fusion. After 24 hours of androgen treatment, TMPRSS2-ERG mRNA level was increased in VCaP cells. PSMA mRNA level was dramatically decreased in VCaP cells, while it only has moderate change in LNCaP cells. Treatment with the androgen antagonist flutamide partially restored PSMA expression in androgen-treated VCaP cells. Knocking down ERG by siRNA in VCaP cells enhances PSMA expression both in the presence and absence of synthetic androgen R1881. Overexpressing TMPRSS2-ERG fusions in LNCaP cells downregulated PSMA both in the presence or absence of R1881, while overexpressing wild type ERG did not. Using PSMA-based luciferase reporter assays, we found TMPRSS2-ERG fusion can inhibit PSMA activity at the transcriptional level. Our data indicated that downregulation of PSMA in androgen-treated VCaP cells appears partially mediated by TMPRSS2-ERG gene fusion.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Fusión Génica , Proteínas de Fusión Oncogénica/genética , Antígeno Prostático Específico/genética , Secuencia de Bases , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Fusión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Luciferasas/metabolismo , Masculino , Metribolona/farmacología , Datos de Secuencia Molecular , Antígeno Prostático Específico/antagonistas & inhibidores , Antígeno Prostático Específico/metabolismo , ARN Interferente Pequeño/metabolismoRESUMEN
Prostate-specific membrane antigen (PSMA) is a membrane protein that is overexpressed manifold in prostate cancer and provides an attractive target for therapy. PSMA ADC is an antibody-drug conjugate (ADC) that consists of a fully human anti-PSMA monoclonal antibody conjugated to monomethylauristatin E through a valine-citrulline linker. In this study, the antitumor activity of PSMA ADC was evaluated against a panel of prostate cancer cell lines in vitro and in a novel in vivo model of taxane-refractory human prostate cancer. In vitro cell killing was efficient for cells with abundant PSMA expression (>10(5) molecules/cell; IC(50) ≤ 0.022 nmol/L) and 1,000-fold less efficient for cells with undetectable PSMA (IC(50) > 30 nmol/L). Intermediate potency (IC(50) = 0.80 nmol/L) was observed for cells with approximately 10(4) molecules of PSMA per cell, indicating a threshold PSMA level for selective cell killing. Similar in vitro activity was observed against androgen-dependent and -independent cells that had abundant PSMA expression. In vitro activity of PSMA ADC was also dependent on internalization and proper N-glycosylation/folding of PSMA. In contrast, less potent and nonselective cytotoxic activity was observed for a control ADC, free monomethylauristatin E, and other microtubule inhibitors. PSMA ADC showed high in vivo activity in treating xenograft tumors that had progressed following an initial course of docetaxel therapy, including tumors that were large (>700 mm(3)) before treatment with PSMA ADC. This study defines determinants of antitumor activity of a novel ADC. The findings here support the clinical evaluation of this agent in advanced prostate cancer.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Antígenos de Neoplasias/inmunología , Antineoplásicos/farmacología , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Inmunoconjugados/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Aminobenzoatos/química , Animales , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/toxicidad , Anticuerpos Monoclonales Humanizados , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Antígenos de Superficie/inmunología , Antígenos de Superficie/metabolismo , Antineoplásicos/uso terapéutico , Antineoplásicos/toxicidad , Línea Celular Tumoral , Modelos Animales de Enfermedad , Glutamato Carboxipeptidasa II/inmunología , Glutamato Carboxipeptidasa II/metabolismo , Humanos , Inmunoconjugados/uso terapéutico , Inmunoconjugados/toxicidad , Estimación de Kaplan-Meier , Masculino , Ratones , Ratones Desnudos , Proteínas Mutantes/genética , Proteínas Mutantes/inmunología , Proteínas Mutantes/metabolismo , Estadificación de Neoplasias , Oligopéptidos/química , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: Retrospective analyses were undertaken to assess the hypothesis that environmental variables influenced immunophysiological status of lacrimal glands from untreated female rabbits that had been housed out-of-doors until they were acquired for use as controls for experimental studies. MATERIALS AND METHODS: Rabbits were euthanized within 5 days of arrival at University Vivaria. Glands were divided for histology and RNA extraction. Transcript abundances were determined with real time RT-PCR. Sections were stained for CD18 and rabbit thymic lymphocyte antigen. Environmental variables assessed were mean daily high temperature, low humidity, high temperature/low humidity ratio, and days with above average temperature/humidity ratio ("adverse days") during the prior 30 days. RESULTS: Spearman's analyses revealed numerous significant correlations. Numbers of T cells and abundances of mRNAs for CD8; CCL2, and CCL4; IL-1α and IL-1ß; the T(H)1 cytokine, IL-2; and the T(H)2- and B cell cytokines, IL-4, IL-6, IL-10, APRIL, and BAFF, all increased with adverse days, while IFN-γ mRNA abundance decreased. Glands from the group exposed to the most adverse days remained free of immunopathological lesions. Glands from the group exposed to the highest temperatures fell above the regression curves for IL-4, APRIL, and BAFF calculated for the other groups and had significantly higher abundances of mRNAs for prolactin, IL-18, CCL21, CCL28, CXCL8, and CXCL13. One of six glands from this group contained small immune cell aggregates; the others appeared normal. The only gland that presented with frank histopathology was from a group that had experienced benign conditions. CONCLUSIONS: Increasing adverse days correlated with increasing abundances of transcripts, including mRNAs for IL-2, IL-10, and CD8, outside the T(H)1/T(H)2 paradigm. The findings raise intriguing questions as to whether and how such changes might be associated with homeostatic phenomena.
Asunto(s)
Citocinas/genética , Ambiente , Genes MHC Clase II/fisiología , Aparato Lagrimal/inmunología , Animales , Antígenos CD8/genética , Dacriocistitis/inmunología , Síndromes de Ojo Seco/inmunología , Femenino , ARN Mensajero/metabolismo , Conejos , Estudios Retrospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células TH1/inmunología , Células Th2/inmunologíaRESUMEN
Several potent prostate specific membrane antigen (PSMA) inhibitors have been described recently. We generated a PSMA-specific 2-5A ligand called RBI 1033 by linking 2-5A to the N-acetylaspartylglutamate (NAAG)-based inhibitor ZJ-24. We measured the inhibitory activity of RBI 1033 to the folate hydrolase activity of PSMA. Amazingly, we found that compared to ZJ-24 (IC50 = 53.9 nM), RBI 1033 was more than 10 times more potent (IC50 = 4.78 nM) as a folate hydrolase inhibitor, while SMCC 2-5A lacking the ZJ-24 part, did not show much activity (IC50 = 1974 nM). Also, RBI 1033's affinity to PSMA was found to be 10 times higher than ZJ-24 itself.
Asunto(s)
Nucleótidos de Adenina/farmacología , Antineoplásicos/farmacología , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Neoplasias de la Próstata/tratamiento farmacológico , Nucleótidos de Adenina/química , Nucleótidos de Adenina/uso terapéutico , Antígenos de Superficie/química , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Endorribonucleasas/química , Glutamato Carboxipeptidasa II/química , Humanos , Ligandos , Masculino , Neoplasias de la Próstata/enzimologíaRESUMEN
Over a half century ago, Charles Huggins demonstrated the response of prostate cancer to androgen deprivation therapy. Subsequently, many discoveries and evolving findings continued to support a research rationale focused on the androgen receptor (AR) as a key target for prostate cancer. More recently, preliminary trials have suggested that other targets could also be useful in the treatment of prostate cancer, and the proposed strategies for treatment have ranged from targeted toxins to immunotherapeutic agents. We provide an overview of some of these approaches, with an emphasis on those that employ prostate specific membrane antigen (PSMA) as a target.
Asunto(s)
Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Andrógenos/metabolismo , Animales , Antígenos de Superficie/química , Membrana Celular/metabolismo , Glutamato Carboxipeptidasa II/química , Humanos , Sistema Inmunológico , Inmunohistoquímica , Inmunoterapia/métodos , Ligandos , Masculino , Modelos Biológicos , Antígeno Prostático Específico/metabolismo , Receptores Androgénicos/metabolismo , Receptores de Antígenos/química , Linfocitos T/metabolismoRESUMEN
PURPOSE: Prostate-specific membrane antigen (PSMA) is an attractive target for active immunotherapy. Alphavirus vaccines have shown promise in eliciting immunity to tumor antigens. This study investigated the immunogenicity of alphavirus vaccine replicon particles (VRP) that encode PSMA (PSMA-VRP). EXPERIMENTAL DESIGN: Cells were infected with PSMA-VRP and evaluated for PSMA expression and folate hydrolase activity. Mice were immunized s.c. with PSMA-VRP or purified PSMA protein. Sera, splenocytes, and purified T cells were evaluated for the magnitude, durability, and epitope specificity of the anti-PSMA response. Antibodies were measured by flow cytometry, and cellular responses were measured by IFN-gamma enzyme-linked immunospot and chromium release assays. Cellular responses in BALB/c and C57BL/6 mice were mapped using overlapping 15-mer PSMA peptides. A Good Laboratory Practice-compliant toxicology study was conducted in rabbits. RESULTS: PSMA-VRP directed high-level expression of active PSMA. Robust T-cell and B-cell responses were elicited by a single injection of 2 x 10(5) infectious units, and responses were boosted following repeat immunizations. Anti-PSMA responses were detected following three immunizations with 10(2) infectious units and increased with increasing dose. PSMA-VRP was more immunogenic than adjuvanted PSMA protein. Responses to PSMA-VRP were characterized by Th-1 cytokines, potent CTL activity, and IgG2a/IgG2b antibodies. T-cell responses in BALB/c and C57BL/6 mice were directed toward different PSMA peptides. Immunogenic doses of PSMA-VRP were well tolerated in mice and rabbits. CONCLUSIONS: PSMA-VRP elicited potent cellular and humoral immunity in mice, and specific anti-PSMA responses were boosted on repeat dosing. PSMA-VRP represents a promising approach for immunotherapy of prostate cancer.
Asunto(s)
Alphavirus/genética , Antígenos de Superficie/genética , Vacunas contra el Cáncer/química , Glutamato Carboxipeptidasa II/genética , Animales , Antígenos de Superficie/química , Epítopos/química , Glutamato Carboxipeptidasa II/química , Sistema Inmunológico , Inmunoterapia/métodos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Péptidos/química , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/terapia , Conejos , Linfocitos T Citotóxicos/metabolismoRESUMEN
Prostate cancer is the most common non-cutaneous cancer of men in the United States and represents their second-leading cause of cancer-related death. Metastatic disease is largely resistant to conventional chemotherapies, and targeted therapies are urgently needed. Prostate-specific membrane antigen (PSMA) is a prototypical cell-surface marker of prostate cancer. PSMA is an integral, non-shed, type 2 membrane protein with abundant and nearly universal expression in prostate carcinoma, but has limited extra-prostatic expression. In addition, PSMA is expressed in the neovasculature of other solid tumors. These findings have spurred development of PSMA-targeted therapies for cancer, and first-generation products have entered clinical testing. Vaccine approaches have included recombinant protein, nucleic acid and cell-based strategies, and anti-PSMA immune responses have been demonstrated in the absence of significant toxicity. Therapy with drug-conjugated and radiolabeled antibodies has yielded objective clinical responses as measured by reductions in serum prostate-specific antigen and/or imageable tumor volume. However, responses were observed in a minor fraction of patients and at doses near the maximum tolerated dose. Overall, these initial studies have provided measured proof of concept for PSMA-based therapies, and second-generation antibody and vaccine products may hold the key to exploit PSMA for molecularly targeted therapy of prostate and other cancers.
Asunto(s)
Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto , Antígeno Prostático Específico/antagonistas & inhibidores , Neoplasias de la Próstata/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Humanos , Inmunoconjugados/uso terapéutico , Masculino , RadioinmunoterapiaRESUMEN
Excessive glutamate release is associated with neuronal damage. A new strategy for the treatment of neuronal injury involves inhibition of the neuropeptidase glutamate carboxypeptidase II (GCP II), also known as N-acetylated alpha-linked acidic dipeptidase. GCP II is believed to mediate the hydrolysis of N-acetyl-aspartyl-glutamate (NAAG) to glutamate and N-acetyl-aspartate, and inhibition of NAAG peptidase activity (by GCP II and other peptidases) is neuroprotective. Mice were generated in which the Folh1 gene encoding GCP II was disrupted (Folh1-/- mice). No overt behavioral differences were apparent between Folh1-/- mice and wild-type littermates, with respect to their overall performance in locomotion, coordination, pain threshold, cognition and psychiatric behavioral paradigms. Morphological analysis of peripheral nerves, however, showed significantly smaller axons (reduced myelin sheaths and axon diameters) in sciatic nerves from Folh1-/- mice. Following sciatic nerve crush, Folh1-/- mice suffered less injury and recovered faster than wild-type littermates. In a model of ischemic injury, the Folh1-/- mice exhibited a significant reduction (p < 0.05) in infarct volume compared with their wild-type littermates when subjected to middle cerebral artery occlusion, a model of stroke. These findings support the hypothesis that GCP II inhibitors may represent a novel treatment for peripheral neuropathies as well as stroke.
Asunto(s)
Isquemia Encefálica/enzimología , Glutamato Carboxipeptidasa II/deficiencia , Glutamato Carboxipeptidasa II/genética , Enfermedades del Sistema Nervioso Periférico/enzimología , Animales , Conducta Animal/fisiología , Isquemia Encefálica/genética , Isquemia Encefálica/patología , Electrofisiología , Infarto de la Arteria Cerebral Media/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Esquelético/patología , Compresión Nerviosa , Enfermedades del Sistema Nervioso Periférico/genética , Enfermedades del Sistema Nervioso Periférico/patología , Fenotipo , Desempeño Psicomotor/fisiología , Nervio Ciático/patologíaRESUMEN
Prostate-specific membrane antigen (PSMA) is a prototypical differentiation antigen expressed on normal and neoplastic prostate epithelial cells, and on the neovasculature of many solid tumors. Monoclonal antibodies specific for PSMA are in development as therapeutic agents. Methodologies to actively immunize against PSMA may be limited by immunologic ignorance and/or tolerance that restrict the response to self-antigens. Our studies have previously shown that xenogeneic immunization with DNA vaccines encoding melanosomal differentiation antigens induces immunity in a mouse melanoma model. Here we apply this approach to PSMA to establish proof of principle in a mouse model. Immunization with xenogeneic human PSMA protein or DNA induced antibodies to both human and mouse PSMA in mice. Monoclonal antibodies specific for mouse PSMA were generated to analyze antibody isotypes and specificity for native and denatured PSMA at the clonal level. Most antibodies recognized denatured PSMA, but C57BL/6 mice immunized with xenogeneic PSMA DNA followed by a final boost with xenogeneic PSMA protein yielded autoantibodies that reacted with native folded mouse PSMA. Monoclonal antibodies were used to confirm the expression of PSMA protein in normal mouse kidney. These results establish the basis for clinical trials to test PSMA DNA vaccines in patients with solid tumors that either express PSMA directly or that depend on normal endothelial cells expressing PSMA for their continued growth.
Asunto(s)
Anticuerpos Heterófilos/inmunología , Antígenos de Superficie/biosíntesis , Antígenos de Superficie/inmunología , Autoanticuerpos/inmunología , Glutamato Carboxipeptidasa II/biosíntesis , Glutamato Carboxipeptidasa II/inmunología , Neoplasias de la Próstata/inmunología , Animales , Formación de Anticuerpos , Modelos Animales de Enfermedad , Células Endoteliales , Perfilación de la Expresión Génica , Humanos , Inmunización/veterinaria , Inmunoterapia/métodos , Masculino , Ratones , Neoplasias de la Próstata/veterinaria , Vacunas de ADNRESUMEN
Prostate-specific membrane antigen (PSMA), a type II transmembrane glycoprotein, is overexpressed in prostate cancer. PSMA is a unique cell surface marker, negatively regulated by androgen and extensively used for imaging of hormone refractory carcinomas and metastatic foci. PSMA is a carboxypeptidase with two important enzymatic functions, namely, folate hydrolase and NAALADase. PSMA also exhibits an endocytic function, in which it spontaneously recycles through endocytic vesicles. PSMA is overexpressed at various stages of prostate cancer, including androgen-sensitive and -independent disease, increased in expression with early relapse after therapy. We have used in vitro invasion assays to explore the possible role of PSMA in the metastasis of prostate cancer cells. Androgen-dependent prostate cancer lines, which express PSMA endogenously (e.g., LNCaP, MDA PCa2b, and CWR22Rv1) are less invasive compared with androgen-independent PC3 or DU145 cells, neither of which expresses PSMA. Ectopic expression of PSMA in PC3 cells reduced the invasiveness of these cells, suggesting that this reduction in the invasion capability of PSMA-expressing cells is due to PSMA expression and not to intrinsic properties of different prostate cancer cell lines. Furthermore, knockdown of PSMA expression increased invasiveness of LNCaP cells by 5-fold. Finally, expression of PSMA mutants lacking carboxypeptidase activity reduced the impact of PSMA expression on invasiveness. Thus, it seems that the enzymatic activity is associated with the effect of PSMA on invasiveness.
Asunto(s)
Antígenos de Superficie/fisiología , Glutamato Carboxipeptidasa II/fisiología , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/patología , Antígenos de Superficie/biosíntesis , Línea Celular Tumoral , Glutamato Carboxipeptidasa II/biosíntesis , Glutamato Carboxipeptidasa II/deficiencia , Humanos , Masculino , Invasividad Neoplásica , Neoplasias de la Próstata/inmunologíaRESUMEN
Prostate specific membrane antigen (PSMA), is a unique membrane bound glycoprotein, which is overexpressed manifold on prostate cancer as well as neovasculature of most of the solid tumors, but not in the vasculature of the normal tissues. This unique expression of PSMA makes it an important marker as well as a large extracellular target of imaging agents. PSMA can serve as target for delivery of therapeutic agents such as cytotoxins or radionuclides. PSMA has two unique enzymatic functions, folate hydrolase and NAALADase and found to be recycled like other membrane bound receptors through clathrin coated pits. The internalization property of PSMA leads one to consider the potential existence of a natural ligand for PSMA. In this review we have discussed the regulation of PSMA expression within the cells, and significance of its expression in prostate cancer and metastasis.
Asunto(s)
Antígenos de Superficie/fisiología , Glutamato Carboxipeptidasa II/fisiología , Neoplasias de la Próstata/fisiopatología , Empalme Alternativo/genética , Animales , Antígenos de Superficie/genética , Proteínas Contráctiles/fisiología , Dipéptidos/metabolismo , Endocitosis/fisiología , Elementos de Facilitación Genéticos/genética , Filaminas , Ácido Fólico/metabolismo , Regulación Neoplásica de la Expresión Génica , Glutamato Carboxipeptidasa II/genética , Humanos , Masculino , Ratones , Proteínas de Microfilamentos/fisiología , Modelos Biológicos , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismoRESUMEN
BACKGROUND: Currently prostate-specific membrane antigen (PSMA) is showing promise both as an imaging and therapeutic target for occult prostate cancer metastases. First generation antibodies against PSMA are used for the FDA approved Prostascint trade mark monoclonal antibody scan and second generation antibodies are being developed for therapeutic targeting as well as imaging 1. However, there have been reports describing PSMA expression in non-prostatic tissues including kidney, liver, and brain. As we had previously showed the existence of a human PSMA homolog, we set out to determine if this non-prostatic expression was due to expression of the PSMA or another gene. MATERIALS AND METHODS: The PSMA homolog (PSMA-like) cDNA was cloned by screening a liver cDNA library. mRNA expression of the PSMA and PSMA-like genes was determined via Northern blot analysis using two different probes and protein expression confirmed in some tissues via Western blot analysis. Transcriptional regulation of the two genes was examined using reporter constructs driving luciferase expression. RESULTS: The PSMA-like gene possesses 98% identity to the PSMA gene at the nucleotide level and is expressed in kidney and liver under the control of a different promoter to the PSMA gene. The PSMA gene is expressed in several human tissues and is most abundant in the nervous system and the prostate. CONCLUSION: The non-prostatic expression of PSMA should be taken into consideration when designing clinical strategies targeting PSMA.
Asunto(s)
Antígenos de Superficie/análisis , Antígenos de Superficie/genética , Cromosomas Humanos Par 11 , Regulación Neoplásica de la Expresión Génica , Glutamato Carboxipeptidasa II/análisis , Glutamato Carboxipeptidasa II/genética , Neoplasias de la Próstata/genética , Anticuerpos Monoclonales/inmunología , Antígenos de Superficie/biosíntesis , Secuencia de Bases , Northern Blotting , Mapeo Cromosómico , ADN Complementario , Glutamato Carboxipeptidasa II/biosíntesis , Humanos , Radioisótopos de Indio , Masculino , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Prostate-specific membrane antigen (PSMA) is a type 2 integral membrane glycoprotein that serves as an attractive target for cancer immunotherapy by virtue of its abundant and restricted expression on the surface of prostate carcinomas and the neovasculature of most other solid tumors. However, relatively little is known about the molecular structure of this target. Here, we report that PSMA is expressed on tumor cells as a noncovalent homodimer. A truncated PSMA protein, lacking transmembrane and cytoplasmic domains, also formed homodimers, indicating that the extracellular domain is sufficient for dimerization. PSMA dimers but not monomers displayed a native conformation and possessed high-level carboxypeptidase activity. A unique dimer-specific epitope was identified by using one of a panel of novel mAbs. When used to immunize animals, dimer but not monomer elicited antibodies that efficiently recognized PSMA-expressing tumor cells. These findings on PSMA structure and biology may have important implications for active and passive immunotherapy of prostate and other cancers.