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BACKGROUND: Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) can reverse depressive-like symptoms clinically and in experimental models of depression, but the mechanisms of action are unknown. OBJECTIVES: This study investigated the role of dopaminergic mechanisms in MFB stimulation-mediated behavior changes, in conjunction with raclopride administration and micropositron emission tomography (micro-PET). METHODS: Flinders Sensitive Line (FSL) rats were allocated into 4 groups: FSL (no treatment), FSL+ (DBS), FSL.R (FSL with raclopride), and FSL.R+ (FSL with raclopride and DBS). Animals were implanted with bilateral electrodes targeting the MFB and given 11 days access to raclopride in the drinking water with or without concurrent continuous bilateral DBS over the last 10 days. Behavioral testing was conducted after stimulation. A PET scan using [18F]desmethoxyfallypride was performed to determine D2 receptor availability before and after raclopride treatment. Changes in gene expression in the nucleus accumbens and the hippocampus were assessed using quantitative polymerase chain reaction. RESULTS: Micro-PET imaging showed that raclopride administration blocked 36% of the D2 receptor in the striatum, but the relative level of blockade was reduced/modulated by stimulation. Raclopride treatment enhanced depressive-like symptoms in several tasks, and the MFB DBS partially reversed the depressive-like phenotype. The raclopride-treated MFB DBS animals had increased levels of mRNA coding for dopamine receptor D1 and D2 suggestive of a stimulation-mediated increase in dopamine receptors. CONCLUSION: Data suggest that chronic and continuous MFB DBS could act via the modulation of the midbrain dopaminergic transmission, including impacting on the postsynaptic dopamine receptor profile.
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Estimulación Encefálica Profunda/métodos , Depresión/metabolismo , Dopamina/metabolismo , Haz Prosencefálico Medial/metabolismo , Tomografía de Emisión de Positrones/métodos , Racloprida/metabolismo , Animales , Depresión/diagnóstico por imagen , Depresión/terapia , Antagonistas de Dopamina/metabolismo , Antagonistas de Dopamina/farmacología , Antagonistas de Dopamina/uso terapéutico , Masculino , Haz Prosencefálico Medial/diagnóstico por imagen , Haz Prosencefálico Medial/efectos de los fármacos , Racloprida/farmacología , Racloprida/uso terapéutico , Ratas , Roedores/metabolismo , Microtomografía por Rayos X/métodosRESUMEN
A technology that visualizes tumor stem cells with clinically relevant tracers could have a broad impact on cancer diagnosis and treatment. The AC133 epitope of CD133 currently is one of the best-characterized tumor stem cell markers for many intra- and extracranial tumor entities. Here we demonstrate the successful noninvasive detection of AC133(+) tumor stem cells by PET and near-infrared fluorescence molecular tomography in subcutaneous and orthotopic glioma xenografts using antibody-based tracers. Particularly, microPET with (64)Cu-NOTA-AC133 mAb yielded high-quality images with outstanding tumor-to-background contrast, clearly delineating subcutaneous tumor stem cell-derived xenografts from surrounding tissues. Intracerebral tumors as small as 2-3 mm also were clearly discernible, and the microPET images reflected the invasive growth pattern of orthotopic cancer stem cell-derived tumors with low density of AC133(+) cells. These data provide a basis for further preclinical and clinical use of the developed tracers for high-sensitivity and high-resolution monitoring of AC133(+) tumor stem cells.
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Antígenos CD/inmunología , Glicoproteínas/inmunología , Células Madre Neoplásicas/inmunología , Péptidos/inmunología , Tomografía de Emisión de Positrones/métodos , Antígeno AC133 , Animales , Neoplasias Encefálicas/diagnóstico por imagen , Fluorescencia , Glioblastoma/diagnóstico por imagen , Xenoinjertos , Ratones , Imagen Multimodal , Tomografía Computarizada por Rayos XRESUMEN
The metabolic instability and high kidney retention of minigastrin (MG) analogues hamper their suitability for use in peptide-receptor radionuclide therapy of CCK2/gastrin receptor-expressing tumors. High kidney retention has been related to N-terminal glutamic acids and can be substantially reduced by coinjection of polyglutamic acids or gelofusine. The aim of the present study was to investigate the influence of the stereochemistry of the N-terminal amino acid spacer on the enzymatic stability and pharmacokinetics of (111)In-DOTA-(d-Glu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 ((111)In-PP11-D) and (111)In-DOTA-(l-Glu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 ((111)In-PP11-L). Using circular dichroism measurements, we demonstrate the important role of secondary structure on the pharmacokinetics of the two MG analogues. The higher in vitro serum stability together with the improved tumor-to-kidney ratio of the (d-Glu)6 congener indicates that this MG analogue might be a good candidate for further clinical study.
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Gastrinas/farmacocinética , Compuestos Heterocíclicos con 1 Anillo/farmacocinética , Radioisótopos de Indio/farmacocinética , Neoplasias/diagnóstico por imagen , Receptor de Colecistoquinina B/metabolismo , Receptor de Colecistoquinina B/fisiología , Secuencia de Aminoácidos , Animales , Gastrinas/química , Gastrinas/metabolismo , Compuestos Heterocíclicos con 1 Anillo/química , Compuestos Heterocíclicos con 1 Anillo/metabolismo , Humanos , Radioisótopos de Indio/química , Radioisótopos de Indio/metabolismo , Masculino , Neoplasias/diagnóstico , Neoplasias/metabolismo , Tomografía de Emisión de Positrones , Ratas Endogámicas LewRESUMEN
Acute graft-versus-host disease (GvHD) is a complex process involving endothelial damage and neovascularization. Better understanding of the pathophysiology of neovascularization during GvHD could help to target this process while leaving T-cell function intact. Under ischemic conditions, neovascularization is regulated by different micro RNAs (miRs), which potentially play a role in inflamed hypoxic GvHD target organs. We observed strong neovascularization in the murine inflamed intestinal tract (IT) during GvHD. Positron emission tomography imaging demonstrated abundant αvß3 integrin expression within intestinal neovascularization areas. To interfere with neovascularization, we targeted αv integrin-expressing endothelial cells, which blocked their accumulation in the IT and reduced GvHD severity independent of immune reconstitution and graft-versus-tumor effects. Additionally, enhanced neovascularization and αv integrin expression correlated with GvHD severity in humans. Expression analysis of miRs in the inflamed IT of mice developing GvHD identified miR-100 as significantly downregulated. Inactivation of miR-100 enhanced GvHD indicating a protective role for miR-100 via blocking inflammatory neovascularization. Our data from the mouse model and patients indicate that inflammatory neovascularization is a central event during intestinal GvHD that can be inhibited by targeting αv integrin. We identify negative regulation of GvHD-related neovascularization by miR-100, which indicates common pathomechanistic features of GvHD and ischemia.
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Enfermedad Injerto contra Huésped/complicaciones , Inflamación/etiología , Integrina alfaV/metabolismo , Enfermedades Intestinales/etiología , MicroARNs/genética , Neovascularización Patológica , Animales , Western Blotting , Trasplante de Médula Ósea , Femenino , Citometría de Flujo , Enfermedad Injerto contra Huésped/metabolismo , Enfermedad Injerto contra Huésped/patología , Humanos , Técnicas para Inmunoenzimas , Inflamación/metabolismo , Inflamación/patología , Integrina alfaV/genética , Enfermedades Intestinales/metabolismo , Enfermedades Intestinales/patología , Mediciones Luminiscentes , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , MicroARNs/metabolismo , Tomografía de Emisión de Positrones , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
We collected norms on the gender stereotypicality of an extensive list of role nouns in Czech, English, French, German, Italian, Norwegian, and Slovak, to be used as a basis for the selection of stimulus materials in future studies. We present a Web-based tool (available at https://www.unifr.ch/lcg/ ) that we developed to collect these norms and that we expect to be useful for other researchers, as well. In essence, we provide (a) gender stereotypicality norms across a number of languages and (b) a tool to facilitate cross-language as well as cross-cultural comparisons when researchers are interested in the investigation of the impact of stereotypicality on the processing of role nouns.
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Identidad de Género , Lenguaje , Adolescente , Adulto , Comparación Transcultural , República Checa , Inglaterra , Femenino , Francia , Alemania , Humanos , Internet , Italia , Masculino , Persona de Mediana Edad , Noruega , Eslovaquia , Adulto JovenRESUMEN
Radiolabeled hybrid ligands with defined distances between an agonist and an antagonist for the gastrin-releasing peptide receptor were found to have excellent tumor-targeting properties. Oligoprolines served as rigid scaffolds that allowed for tailoring distances of 10, 20, and 30 Å between the recognition elements. In vitro and in vivo studies revealed that the hybrid ligand with a distance of 20 Å between the recognition elements exhibits the highest yet observed tumor cell uptake and retention time in prostate cancer cells.
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Bombesina/análogos & derivados , Bombesina/farmacocinética , Sistemas de Liberación de Medicamentos , Neoplasias de la Próstata/tratamiento farmacológico , Receptores de Bombesina/agonistas , Receptores de Bombesina/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Humanos , Masculino , Ratones , Ratones Desnudos , Prolina/análogos & derivados , Prolina/farmacocinética , Receptores de Bombesina/metabolismoRESUMEN
BACKGROUND: One of the most important biological characteristics of Glioblastoma multiforme (GBM) is high vascular density. Vadimezan (ASA404, DMXAA) belongs to the class of small molecule vascular disrupting agents (VDA) that cause disruption of established tumor vessels and subsequent tumor hemorrhagic necrosis. Its selective antivascular effect is mediated by intratumoral induction of several cytokines including tumor necrosis factor-α (TNF-α), granulocyte-colony-stimulating factor (G-CSF), interleukin 6 (IL-6) and macrophage inflammatory protein 1α (MIP-1α). Preclinical studies have demonstrated that ASA404 acts synergistically with taxanes. In this study, we investigated if treatment of mice bearing U251 human glioblastoma xenografts with ASA404 and taxol may be synergistic. Therapy response was evaluated by measuring changes in tumor size and metabolic activity using 18F-FDG PET (Fluorodeoxyglucose - positron emision tomography) imaging. METHODS: U251 cells were inoculated s.c. in the right hind limb of NMRI-Foxn1nu athymic female nude mice. Animals were randomly assigned into 4 groups (7-9 animals/group) for treatment: control, taxol, ASA404, and ASA404 plus taxol. The animals received either a single dose of taxol (10 mg/kg), ASA404 (27.5 mg/kg), or taxol (10 mg/kg) plus ASA404 (27.5 mg/kg) administered i.p.; ASA404 was administred 24 h after the treatment with taxol. 4 and 24 h after treatment with ASA404 (28 and 48 h hours after treatment with taxol) 18 F-FDG PET scans were performed. RESULTS: The treatment with taxol did not affect the tumor growth in comparison to untreated controls. The treatment of animals with single dose ASA404 alone or in combination with taxol caused a significant delay in tumor growth. The combined treatment did not decrease the growth of the xenografts significantly more than ASA404 alone, but early changes in tumor 18 F-FDG uptake preceded subsequent growth inhibition. The tumor weights, which were determined at the end of treatment, were lower in case of combined treatment. CONCLUSIONS: The treatment with ASA404 alone or in combination with taxol showed antitumoral effects in our glioblastoma model probably through destruction of blood vessels. The implications for the anticancer effect of this compound warrant further preclinical studies. 18F-FDG PET appears to be a promising tool to monitor treatment with ASA404 early in the course of therapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Glioblastoma/tratamiento farmacológico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Peso Corporal/efectos de los fármacos , Línea Celular Tumoral , Femenino , Fluorodesoxiglucosa F18 , Glioblastoma/diagnóstico , Humanos , Ratones , Ratones Desnudos , Paclitaxel/administración & dosificación , Tomografía de Emisión de Positrones , Carga Tumoral/efectos de los fármacos , Xantonas/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Psycholinguistic investigations of the way readers and speakers perceive gender have shown several biases associated with how gender is linguistically realized in language. Although such variations across languages offer interesting grounds for legitimate cross-linguistic comparisons, pertinent characteristics of grammatical systems - especially in terms of their gender asymmetries - have to be clearly identified. In this paper, we present a language index for researchers interested in the effect of grammatical gender on the mental representations of women and men. Our index is based on five main language groups (i.e., grammatical gender languages, languages with a combination of grammatical gender and natural gender, natural gender languages, genderless languages with few traces of grammatical gender and genderless languages) and three sets of specific features (morphology, masculine-male generics and asymmetries). Our index goes beyond existing ones in that it provides specific dimensions relevant to those interested in psychological and sociological impacts of language on the way we perceive women and men. We also offer a critical discussion of any endeavor to classify languages according to grammatical gender.
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Different environmental conditions under anesthesia may lead to unstable homeostatic conditions in rodents and therefore may alter kinetics. In this study, the impact of different heating conditions on PET imaging quantification was evaluated. Methods: Two groups of 6 adult female BALB/c nude mice with subcutaneously implanted tumors underwent microPET imaging after injection of 18F-labeled tetrafluoroborate or 18F-FDG. Dynamic scans were acquired under optimal and suboptimal heating conditions. Time-activity curves were analyzed to calculate uptake and washout time constants. Results: With 18F-labeled tetrafluoroborate, optimal animal heating led to a stable heart rate during acquisition (515 ± 35 [mean ± SD] beats/min), whereas suboptimal heating led to a lower heart rate and a higher SD (470 ± 84 beats/min). Both uptake and washout time constants were faster (P < 0.01) in animals maintained with optimal heating. Conclusion: Although the difference in heart rates was slight, optimal heating yielded significantly faster uptake and washout kinetics than suboptimal heating in all organs for both tracers.
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Temperatura Corporal , Ácidos Bóricos/farmacocinética , Fluorodesoxiglucosa F18/farmacocinética , Frecuencia Cardíaca , Neoplasias/metabolismo , Tomografía de Emisión de Positrones/métodos , Animales , Boratos , Femenino , Calefacción , Tasa de Depuración Metabólica , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias/diagnóstico por imagen , Especificidad de Órganos , Radiofármacos/farmacocinética , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Distribución TisularRESUMEN
Checkpoint-blocking antibodies like those targeting the PD-1/PD-L1 pathway have revolutionized oncology. We developed radiotracers based on therapeutic checkpoint-blocking antibodies permitting sensitive and high-resolution PET imaging of both PD-1 and PD-L1 in immunocompetent mice. ImmunoPET of naive mice revealed similar overall expression patterns for PD-1 and PD-L1 in secondary lymphoid organs (spleen and lymph nodes). Interestingly, PD-L1 was also detected in brown adipose tissue (BAT), confirming the notion that BAT is immunologically relevant. Under pathophysiological conditions, strong expression of the receptor/ligand pair was also found in non-lymphoid tissues. Both were specifically detected in malignant tumors. PD-1 was readily detected after combined immunoradiotherapy causing massive tumor infiltration by PD-1+ lymphocytes. PD-L1 tracer uptake was reduced in PD-L1 knockout tumors. Moreover, monitoring the expression changes of PD-L1 in response to its main inducer, the effector T cell cytokine IFN-γ, revealed robust upregulation in the lung. This suggests that T cell responses in the lung, a vital organ continuously exposed to a variety of antigens, are strongly restrained by the PD-1 checkpoint. In turn, this could explain the association of PD-1 checkpoint inhibition with potentially fatal immune-mediated pneumonitis and partially also its efficacy in lung cancer.
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Anticuerpos/administración & dosificación , Antígeno B7-H1/análisis , Factores Inmunológicos/administración & dosificación , Tomografía de Emisión de Positrones/métodos , Receptor de Muerte Celular Programada 1/análisis , Animales , Antígeno B7-H1/inmunología , Ratones , Receptor de Muerte Celular Programada 1/inmunologíaRESUMEN
Small cell lung cancer (SCLC) is an aggressive tumor with poor prognosis due to early metastatic spread and development of chemoresistance. Playing a key role in tumor-stroma interactions the CXCL12-CXCR4 axis may be involved in both processes and thus represent a promising therapeutic target in SCLC treatment. In this study we investigated the effect of CXCR4 inhibition on metastasis formation and chemoresistance using an orthotopic xenograft mouse model. This model demonstrates regional spread and spontaneous distant metastases closely reflecting the clinical situation in extensive SCLC. Tumor engraftment, growth, metabolism, and metastatic spread were monitored using different imaging techniques: Magnetic Resonance Imaging (MRI), Bioluminescence Imaging (BLI) and Positron Emission Tomography (PET). Treatment of mice bearing chemoresistant primary tumors with the specific CXCR4 inhibitor AMD3100 reduced the growth of the primary tumor by 61% (P<0.05) and additionally suppressed metastasis formation by 43%. In comparison to CXCR4 inhibition as a monotherapy, standard chemotherapy composed of cisplatin and etoposide reduced the growth of the primary tumor by 71% (P<0.01) but completely failed to suppress metastasis formation. Combination of chemotherapy and the CXCR4 inhibitor integrated the highest of both effects. The growth of the primary tumor was reduced to a similar extent as with chemotherapy alone and metastasis formation was reduced to a similar extent as with CXCR4 inhibitor alone. In conclusion, we demonstrate in this orthotopic mouse model that the addition of a CXCR4 inhibitor to chemotherapy significantly reduces metastasis formation. Thus, it might improve the overall therapy response and consequently the outcome of SCLC patients.
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Compuestos Heterocíclicos/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Péptidos/uso terapéutico , Receptores CXCR4/antagonistas & inhibidores , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Animales , Bencilaminas , Carcinogénesis , Línea Celular Tumoral , Movimiento Celular , Cisplatino/uso terapéutico , Ciclamas , Proteínas de Unión al ADN/genética , Resistencia a Antineoplásicos , Etopósido/uso terapéutico , Compuestos Heterocíclicos/farmacología , Humanos , Ratones , Ratones Noqueados , Metástasis de la Neoplasia , Proteínas Nucleares/genética , Péptidos/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Small cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer with very poor prognosis due to early metastatic spread and development of chemoresistance. In the last 30 years the study of SCLC has been constrained by a lack of primary human tumor specimen thus highlighting the need of a suitable mouse model. In this article we present the establishment of an orthotopic xenograft mouse model which accurately reproduced the clinical course of SCLC. Orthotopic implantation enabled engraftment of primary lung tumors in all injected mice. Furthermore, immunodeficiency of mice allowed formation of spontaneous metastases in characteristic organs. Bioluminescence Imaging, Magnetic Resonance Imaging and Positron emission tomography were applied to monitor engraftment, metabolism and the exact growth of tumors over time. In order to mimic the extensive disease stage, mice were injected with aggressive human chemoresistant cells leading to development of chemoresistant tumors and early metastatic spread. As a proof of concept treatment of tumor-bearing mice with conventional chemotherapeutics reduced tumor volumes, but a complete regression of tumors was not achieved. By mimicking the extensive disease stage our mouse model can facilitate the study of mechanisms contributing to chemoresistance and metastasis formation, as well as drug screening and evaluation of new treatment strategies for SCLC patients.
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Modelos Animales de Enfermedad , Metástasis de la Neoplasia/patología , Carcinoma Pulmonar de Células Pequeñas/patología , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Resistencia a Antineoplásicos/genética , Humanos , Pulmón , Imagen por Resonancia Magnética , Ratones , Metástasis de la Neoplasia/diagnóstico por imagen , Metástasis de la Neoplasia/genética , Carcinoma Pulmonar de Células Pequeñas/diagnóstico por imagen , Carcinoma Pulmonar de Células Pequeñas/genética , Trasplante Heterólogo/métodosRESUMEN
Cancer stem cells (CSC) drive tumorigenesis and contribute to genotoxic therapy resistance, diffuse infiltrative invasion, and immunosuppression, which are key factors for the incurability of glioblastoma multiforme (GBM). The AC133 epitope of CD133 is an important CSC marker for GBM and other tumor entities. Here, we report the development and preclinical evaluation of a recombinant AC133×CD3 bispecific antibody (bsAb) that redirects human polyclonal T cells to AC133(+) GBM stem cells (GBM-SC), inducing their strong targeted lysis. This novel bsAb prevented the outgrowth of AC133-positive subcutaneous GBM xenografts. Moreover, upon intracerebral infusion along with the local application of human CD8(+) T cells, it exhibited potent activity in prophylactic and treatment models of orthotopic GBM-SC-derived invasive brain tumors. In contrast, normal hematopoietic stem cells, some of which are AC133-positive, were virtually unaffected at bsAb concentrations effective against GBM-SCs and retained their colony-forming abilities. In conclusion, our data demonstrate the high activity of this new bsAb against patient-derived AC133-positive GBM-SCs in models of local therapy of highly invasive GBM.
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Anticuerpos Biespecíficos/uso terapéutico , Antígenos CD/inmunología , Glioblastoma/terapia , Glicoproteínas/inmunología , Células Madre Neoplásicas/inmunología , Péptidos/inmunología , Antígeno AC133 , Anticuerpos Biespecíficos/inmunología , Antígenos CD/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Carcinogénesis/inmunología , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Epítopos/inmunología , Glioblastoma/inmunología , Glioblastoma/patología , Glicoproteínas/uso terapéutico , Humanos , Inmunoterapia/métodos , Células Madre Neoplásicas/patología , Péptidos/uso terapéuticoRESUMEN
UNLABELLED: In recent years, there has been a growing interest in molecular imaging markers of tumor-induced angiogenesis. Several radiolabeled RGD (arginine, glycine, aspartate) peptides have been developed for PET imaging of αvß3 integrins in the tumor vasculature, but there are only limited data on how angiogenesis inhibitors affect the tumor uptake of these peptides. METHODS: Changes in (68)Ga-NODAGA-c(RGDfK) peptide uptake were measured using PET during bevacizumab therapy of 2 αvß3-negative squamous cell carcinoma cell lines (A-431 and FaDu) that induce αvß3-positive neovasculature when transplanted into nude mice. Tumor uptake of (68)Ga-NODAGA-c(RGDfK) was correlated to microvascular density, vascular morphology, and permeability as well as αvß3 integrin expression. RESULTS: Bevacizumab significantly inhibited growth of A-431 tumors and caused a significant reduction in microvascular density and αvß3 integrin expression within 7 d after start of therapy. Bevacizumab also caused a normalization of blood vessel morphology and decreased tumor necrosis. However, (68)Ga-NODAGA-c(RGDfK) uptake was significantly increased at day 7 of therapy and did not decrease until after 3 wk of treatment. In Fadu xenografts, bevacizumab therapy caused only a minor inhibition of tumor growth and minor changes in (68)Ga-NODAGA-c(RGDfK) uptake. CONCLUSION: Uptake of radiolabeled RGD peptides is not necessarily decreased by effective antiangiogenic therapy. Early in the course of therapy a decrease in the expression of αvß3 integrins may not be reflected by a decrease in the uptake of RGD peptides.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/tratamiento farmacológico , Integrina alfaVbeta3/metabolismo , Neovascularización Patológica , Tomografía de Emisión de Positrones , Acetatos , Algoritmos , Inhibidores de la Angiogénesis/química , Animales , Bevacizumab , Línea Celular Tumoral , Femenino , Radioisótopos de Galio/química , Compuestos Heterocíclicos con 1 Anillo , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Microcirculación , Necrosis , Trasplante de Neoplasias , Oligopéptidos/química , Péptidos/química , Permeabilidad , Factores de TiempoRESUMEN
UNLABELLED: The gastrin-releasing peptide receptor (GRPr) is overexpressed in prostate cancer and is an attractive target for radionuclide therapy. In addition, inhibition of the protein kinase mammalian target of rapamycin (mTOR) has been shown to sensitize various cancer cells to the effects of radiotherapy. METHODS: To determine the effect of treatment with rapamycin and radiotherapy with a novel (177)Lu-labeled GRPr antagonist ((177)Lu-RM2, BAY 1017858) alone and in combination, in vitro and in vivo studies were performed using the human PC-3 prostate cancer cell line. PC-3 cell proliferation and (177)Lu-RM2 uptake after treatment with rapamycin were assessed in vitro. To determine the influence of rapamycin on (177)Lu-RM2 tumor uptake, in vivo small-animal PET studies with (68)Ga-RM2 were performed after treatment with rapamycin. To study the efficacy of (177)Lu-RM2 in vivo, mice with subcutaneous PC-3 tumors were treated with (177)Lu-RM2 alone or after pretreatment with rapamycin. RESULTS: Stable expression of GRPr was maintained after rapamycin treatment with doses up to 4 mg/kg in vivo. Monotherapy with (177)Lu-RM2 at higher doses (72 and 144 MBq) was effective in inducing complete tumor remission in 60% of treated mice. Treatment with 37 MBq of (177)Lu-RM2 and rapamycin in combination led to significantly longer survival than with either agent alone. No treatment-related toxicity was observed. CONCLUSION: Radiotherapy using a (177)Lu-labeled GRPr antagonist alone or in combination with rapamycin was efficacious in inhibiting in vivo tumor growth and may be a promising strategy for treatment of prostate cancer.
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Terapia Molecular Dirigida/métodos , Oligopéptidos/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/radioterapia , Receptores de Bombesina/antagonistas & inhibidores , Sirolimus/uso terapéutico , Animales , Línea Celular Tumoral , Terapia Combinada , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Humanos , Lutecio/uso terapéutico , Masculino , Ratones , Oligopéptidos/química , Oligopéptidos/farmacocinética , Oligopéptidos/farmacología , Neoplasias de la Próstata/patología , Radioisótopos/uso terapéutico , Receptores de Bombesina/metabolismo , Sirolimus/farmacologíaRESUMEN
In Huntington's disease (HD) cognitive deficits co-exist with motor impairments, both contributing to the overall disease symptomology. Despite short-term and working memory impairments, learning and other non-motoric behavioral deficits arising from the damage to frontostriatal loop being common in HD patients, most of the experimental work with transgenic animals focuses on motor symptoms. The transgenic rat model (tgHD) recapitulates many hallmark HD-like symptoms, such as huntingtin aggregates, cellular loss and dysfunction, and motor, and some cognitive deficits. In the current study we tested tgHD rats in two different cognitive, water maze competition paradigms to learn more about the impact of the transgene on learning and memory processing using hippocampal- and striatal-based memory systems. The tgHD rats had early and robust cognitive deficits in learning and memory function in both paradigms. Specifically, the transgenic animals were impaired in task acquisition and committed more procedural errors with the strongest phenotype amongst the homozygote tgHD. Although the transgenic animals were capable of using both procedural and declarative memory, their response patterns were distinct from wild-type animals. Wide spread huntingtin aggregates were observed at 13 months, but neither PET nor autoradiography indicated neuronal loss or dysfunction in striatal dopamine receptor population. In summary, the homozygote tgHD showed a robust learning and memory impairment prior to any clear motor deficits, or striatal dysfunction. However, the data were not conclusive regarding how the memory systems were compromised and the precise nature and underlying mechanism of the cognitive deficit in the tgHD model requires further investigation.
Asunto(s)
Modelos Animales de Enfermedad , Neuroimagen Funcional/psicología , Enfermedad de Huntington/genética , Enfermedad de Huntington/psicología , Trastornos de la Memoria/genética , Trastornos de la Memoria/psicología , Animales , Glucemia/genética , Peso Corporal/genética , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Femenino , Radioisótopos de Flúor , Neuroimagen Funcional/métodos , Proteína Huntingtina , Enfermedad de Huntington/complicaciones , Enfermedad de Huntington/diagnóstico por imagen , Masculino , Aprendizaje por Laberinto , Trastornos de la Memoria/complicaciones , Trastornos de la Memoria/diagnóstico por imagen , Actividad Motora/genética , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Tomografía de Emisión de Positrones/métodos , Tomografía de Emisión de Positrones/psicología , Ratas , Ratas Sprague-Dawley , Ratas Transgénicas , Receptores de Dopamina D2/metabolismo , SalicilamidasRESUMEN
INTRODUCTION: [(18)F]desmethoxyfallypride ([(18)F]DMFP) is a promising tracer for longitudinal assessment of striatal dopamine D2/D3-receptor (D2R) availability by positron emission tomography (PET) in small animal models. We explored the feasibility of [(18)F]DMFP-PET to image D2R availability in rat models of Huntington's (HD) and Parkinson's disease (PD). METHODS: Animals received either unilateral intrastriatal quinolinic acid lesions or medial forebrain bundle injections of 6-OHDA to produce the loss of striatal projection neurones or deplete the striatal dopamine, corresponding to established animal models for HD and PD, respectively. Three weeks after lesioning, PET scans were acquired on a microPET Focus 120 system following the tail vein injection of [(18)F]DMFP. RESULTS: [(18)F]DMFP-PET clearly visualized lesion induced decreases and increases of D2R availability. In vivo estimates of D2R binding and changes thereof gained by pharmacokinetic analyses correlated significantly with D2R density and its change provided by in vitro [(3)H]raclopride-autoradiography. CONCLUSIONS: In conclusion, [(18)F]DMFP-PET is a suitable method for in vivo D2R-assessment in preclinical research, e.g for monitoring cell-based therapies.
Asunto(s)
Enfermedad de Huntington/metabolismo , Enfermedad de Parkinson/metabolismo , Tomografía de Emisión de Positrones/métodos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Salicilamidas , Animales , Modelos Animales de Enfermedad , Enfermedad de Huntington/diagnóstico por imagen , Enfermedad de Parkinson/diagnóstico por imagen , Racloprida/metabolismo , Trazadores Radiactivos , RatasRESUMEN
Chelated somatostatin agonists have been shown to be sensitive to N-terminal radiometal modifications, with Ga-DOTA agonists having significantly higher binding affinity than their Lu-, In-, and Y-DOTA correlates. Recently, somatostatin antagonists have been successfully developed as alternative tracers to agonists. The aim of this study was to evaluate whether chelated somatostatin antagonists are also sensitive to radiometal modifications and how. We have synthesized 3 different somatostatin antagonists, DOTA-p-NO(2)-Phe-c[D-Cys-Tyr-D-Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH(2), DOTA-Cpa-c[D-Cys-Aph(Hor)-D-Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH(2) (DOTA-JR11), and DOTA-p-Cl-Phe-c[D-Cys-Tyr-D-Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH(2), and added various radiometals including In(III), Y(III), Lu(III), Cu(II), and Ga(III). We also replaced DOTA with 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA) and added Ga(III). The binding affinity of somatostatin receptors 1 through 5 was evaluated in all cases. In all 3 resulting antagonists, the Ga-DOTA analogs were the lowest-affinity radioligands, with a somatostatin receptor 2 binding affinity up to 60 times lower than the respective Y-DOTA, Lu-DOTA, or In-DOTA compounds. Interestingly, however, substitution of DOTA by the NODAGA chelator was able to increase massively its binding affinity in contrast to the Ga-DOTA analog. The 3 NODAGA analogs are antagonists in functional tests. In vivo biodistribution studies comparing (68)Ga-DOTATATE agonist with (68)Ga-DOTA-JR11 and (68)Ga-NODAGA-JR11 showed not only that the JR11 antagonist radioligands were superior to the agonist ligands but also that (68)Ga-NODAGA-JR11 was the tracer of choice and preferable to (68)Ga-DOTA-JR11 in transplantable HEK293-hsst(2) tumors in mice. One may therefore generalize that somatostatin receptor 2 antagonists are sensitive to radiometal modifications and may preferably be coupled with a (68)Ga-NODAGA chelator-radiometal complex.