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1.
Pharm Res ; 38(6): 1067-1079, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34100216

RESUMEN

PURPOSE: Glioblastoma (GBM) is a malignant brain tumor with a poor long-term prognosis due to recurrence from highly resistant GBM cancer stem cells (CSCs), for which the current standard of treatment with temozolomide (TMZ) alone will unlikely produce a viable cure. In addition, CSCs regenerate rapidly and overexpress methyl transferase which overrides the DNA-alkylating mechanism of TMZ, leading to resistance. The objective of this research was to apply the concepts of nanotechnology to develop a multi-drug therapy, TMZ and idasanutlin (RG7388, a potent mouse double minute 2 (MDM2) antagonist), loaded in functionalized nanoparticles (NPs) that target the GBM CSC subpopulation, reduce the cell viability and provide possibility of in vivo preclinical imaging. METHODS: Polymer-micellar NPs composed of poly(styrene-b-ethylene oxide) (PS-b-PEO) and poly(lactic-co-glycolic) acid (PLGA) were developed by a double emulsion technique loading TMZ and/or RG7388. The NPs were covalently bound to a 15-nucleotide base-pair CD133 aptamer to target the CD133 antigen expressed on the surfaces of GBM CSCs. For diagnostic functionality, the NPs were labelled with radiotracer Zirconium-89 (89Zr). RESULTS: NPs maintained size range less than 100 nm, a low negative charge and exhibited the ability to target and kill the CSC subpopulation when TMZ and RG7388 were used in combination. The targeting function of CD133 aptamer promoted killing in GBM CSCs providing impetus for further development of targeted nanosystems for localized therapy in future in vivo models. CONCLUSIONS: This work has provided a potential clinical application for targeting GBM CSCs with simultaneous diagnostic imaging.


Asunto(s)
Antígeno AC133/metabolismo , Neoplasias Encefálicas/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Glioblastoma/metabolismo , Nanopartículas/metabolismo , Células Madre Neoplásicas/metabolismo , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Desarrollo de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/métodos , Glioblastoma/tratamiento farmacológico , Humanos , Ratones , Micelas , Nanopartículas/administración & dosificación , Células Madre Neoplásicas/efectos de los fármacos , Polímeros/administración & dosificación , Polímeros/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Pirrolidinas/administración & dosificación , Pirrolidinas/metabolismo , Temozolomida/administración & dosificación , Temozolomida/metabolismo , para-Aminobenzoatos/administración & dosificación , para-Aminobenzoatos/metabolismo
2.
Drug Metab Dispos ; 43(9): 1360-71, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26149830

RESUMEN

Effective treatments for primary brain tumors and brain metastases represent a major unmet medical need. Targeting the CDK4/CDK6-cyclin D1-Rb-p16/ink4a pathway using a potent CDK4 and CDK6 kinase inhibitor has potential for treating primary central nervous system tumors such as glioblastoma and some peripheral tumors with high incidence of brain metastases. We compared central nervous system exposures of two orally bioavailable CDK4 and CDK6 inhibitors: abemaciclib, which is currently in advanced clinical development, and palbociclib (IBRANCE; Pfizer), which was recently approved by the U.S. Food and Drug Administration. Abemaciclib antitumor activity was assessed in subcutaneous and orthotopic glioma models alone and in combination with standard of care temozolomide (TMZ). Both inhibitors were substrates for xenobiotic efflux transporters P-glycoprotein and breast cancer resistant protein expressed at the blood-brain barrier. Brain Kp,uu values were less than 0.2 after an equimolar intravenous dose indicative of active efflux but were approximately 10-fold greater for abemaciclib than palbociclib. Kp,uu increased 2.8- and 21-fold, respectively, when similarly dosed in P-gp-deficient mice. Abemaciclib had brain area under the curve (0-24 hours) Kp,uu values of 0.03 in mice and 0.11 in rats after a 30 mg/kg p.o. dose. Orally dosed abemaciclib significantly increased survival in a rat orthotopic U87MG xenograft model compared with vehicle-treated animals, and efficacy coincided with a dose-dependent increase in unbound plasma and brain exposures in excess of the CDK4 and CDK6 Ki values. Abemaciclib increased survival time of intracranial U87MG tumor-bearing rats similar to TMZ, and the combination of abemaciclib and TMZ was additive or greater than additive. These data show that abemaciclib crosses the blood-brain barrier and confirm that both CDK4 and CDK6 inhibitors reach unbound brain levels in rodents that are expected to produce enzyme inhibition; however, abemaciclib brain levels are reached more efficiently at presumably lower doses than palbociclib and are potentially on target for a longer period of time.


Asunto(s)
Aminopiridinas/farmacología , Bencimidazoles/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Glioblastoma/tratamiento farmacológico , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Aminopiridinas/administración & dosificación , Aminopiridinas/uso terapéutico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencimidazoles/administración & dosificación , Bencimidazoles/uso terapéutico , Neoplasias Encefálicas/patología , Dacarbazina/administración & dosificación , Dacarbazina/análogos & derivados , Perros , Femenino , Glioblastoma/patología , Células de Riñón Canino Madin Darby , Masculino , Ratones , Piperazinas/administración & dosificación , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/administración & dosificación , Piridinas/uso terapéutico , Ratas , Temozolomida , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Bioorg Med Chem Lett ; 23(24): 6874-8, 2013 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-24183537

RESUMEN

Using an innovative approach toward multiple carbon-carbon bond-formations that relies on the multifaceted catalytic properties of titanocene complexes we constructed a series of C1-C7 analogs of curcumin for evaluation as brain and peripheral nervous system anti-cancer agents. C2-Arylated analogs proved efficacious against neuroblastoma (SK-N-SH & SK-N-FI) and glioblastoma multiforme (U87MG) cell lines. Similar inhibitory activity was also evident in p53 knockdown U87MG GBM cells. Furthermore, lead compounds showed limited growth inhibition in vitro against normal primary human CD34+hematopoietic progenitor cells. Taken together, the present findings indicate that these curcumin analogs are viable lead compounds for the development of new central and peripheral nervous system cancer chemotherapeutics with the potential for little effects on normal hematopoietic progenitor cells.


Asunto(s)
Antineoplásicos/síntesis química , Curcumina/análogos & derivados , Diseño de Fármacos , Antineoplásicos/química , Antineoplásicos/toxicidad , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Curcumina/síntesis química , Curcumina/toxicidad , Glioblastoma/metabolismo , Glioblastoma/patología , Células Madre Hematopoyéticas/citología , Humanos , Neuroblastoma/metabolismo , Neuroblastoma/patología , Relación Estructura-Actividad , Proteína p53 Supresora de Tumor/deficiencia , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo
4.
Bioorg Med Chem Lett ; 23(23): 6463-6, 2013 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-24140446

RESUMEN

We have explored the decahydroisoquinoline scaffold, bearing a phenyl tetrazole, as GluK1 antagonists with potential as oral analgesics. We have established the optimal linker atom between decahydroisoquinoline and phenyl rings and demonstrated an improvement of both the affinity for the GluK1 receptor and the selectivity against the related GluA2 receptor with proper phenyl substitution. In this Letter, we also disclose in vivo data that led to the discovery of LY545694·HCl, a compound with oral efficacy in two persistent pain models.


Asunto(s)
Isoquinolinas/farmacología , Dolor/tratamiento farmacológico , Profármacos/farmacología , Receptores de Ácido Kaínico/antagonistas & inhibidores , Tetrazoles/farmacología , Administración Oral , Secuencia de Aminoácidos , Animales , Modelos Animales de Enfermedad , Isoquinolinas/química , Masculino , Datos de Secuencia Molecular , Profármacos/química , Ratas , Ratas Sprague-Dawley , Receptores de Ácido Kaínico/química , Relación Estructura-Actividad , Tetrazoles/química
5.
Bioorg Med Chem Lett ; 23(23): 6459-62, 2013 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-24119554

RESUMEN

The synthesis and structure-activity relationship of decahydroisoquinoline derivatives with various benzoic acid substitutions as GluK1 antagonists are described. Potent and selective antagonists were selected for a tailored prodrug approach in order to facilitate the evaluation of the new compounds in pain models after oral administration. Several diester prodrugs allowed for acceptable amino acid exposure and moderate efficacy in vivo.


Asunto(s)
Isoquinolinas/farmacología , Dolor/tratamiento farmacológico , Profármacos/farmacología , Receptores de Ácido Kaínico/antagonistas & inhibidores , Administración Oral , Secuencia de Aminoácidos , Animales , Modelos Animales de Enfermedad , Haplorrinos , Isoquinolinas/química , Datos de Secuencia Molecular , Profármacos/química , Receptores de Ácido Kaínico/química , Relación Estructura-Actividad
6.
Sci Rep ; 13(1): 9163, 2023 06 06.
Artículo en Inglés | MEDLINE | ID: mdl-37280243

RESUMEN

Pleomorphic xanthoastrocytoma (PXA) is a rare subset of primary pediatric glioma with 70% 5-year disease free survival. However, up to 20% of cases present with local recurrence and malignant transformation into more aggressive type anaplastic PXA (AXPA) or glioblastoma. The understanding of disease etiology and mechanisms driving PXA and APXA are limited, and there is no standard of care. Therefore, development of relevant preclinical models to investigate molecular underpinnings of disease and to guide novel therapeutic approaches are of interest. Here, for the first time we established, and characterized a patient-derived xenograft (PDX) from a leptomeningeal spread of a patient with recurrent APXA bearing a novel CDC42SE2-BRAF fusion. An integrated -omics analysis was conducted to assess model fidelity of the genomic, transcriptomic, and proteomic/phosphoproteomic landscapes. A stable xenoline was derived directly from the patient recurrent tumor and maintained in 2D and 3D culture systems. Conserved histology features between the PDX and matched APXA specimen were maintained through serial passages. Whole exome sequencing (WES) demonstrated a high degree of conservation in the genomic landscape between PDX and matched human tumor, including small variants (Pearson's r = 0.794-0.839) and tumor mutational burden (~ 3 mutations/MB). Large chromosomal variations including chromosomal gains and losses were preserved in PDX. Notably, chromosomal gain in chromosomes 4-9, 17 and 18 and loss in the short arm of chromosome 9 associated with homozygous 9p21.3 deletion involving CDKN2A/B locus were identified in both patient tumor and PDX sample. Moreover, chromosomal rearrangement involving 7q34 fusion; CDC42SE-BRAF t (5;7) (q31.1, q34) (5:130,721,239, 7:140,482,820) was identified in the PDX tumor, xenoline and matched human tumor. Transcriptomic profile of the patient's tumor was retained in PDX (Pearson r = 0.88) and in xenoline (Pearson r = 0.63) as well as preservation of enriched signaling pathways (FDR Adjusted P < 0.05) including MAPK, EGFR and PI3K/AKT pathways. The multi-omics data of (WES, transcriptome, and reverse phase protein array (RPPA) was integrated to deduce potential actionable pathways for treatment (FDR < 0.05) including KEGG01521, KEGG05202, and KEGG05200. Both xenoline and PDX were resistant to the MEK inhibitors trametinib or mirdametinib at clinically relevant doses, recapitulating the patient's resistance to such treatment in the clinic. This set of APXA models will serve as a preclinical resource for developing novel therapeutic regimens for rare anaplastic PXAs and pediatric high-grade gliomas bearing BRAF fusions.


Asunto(s)
Astrocitoma , Neoplasias Encefálicas , Glioma , Humanos , Niño , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Xenoinjertos , Fosfatidilinositol 3-Quinasas/genética , Proteómica , Recurrencia Local de Neoplasia/patología , Astrocitoma/patología , Glioma/patología , Mutación , Aberraciones Cromosómicas , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Proteínas de la Membrana/genética , Péptidos y Proteínas de Señalización Intracelular/genética
7.
J Magn Reson Imaging ; 36(2): 459-67, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22517495

RESUMEN

PURPOSE: To evaluate the reproducibility of the measurement of the total choline-to-water ratio, and the effect of repositioning the subject between scans, using (1) H-magnetic resonance spectroscopy in a mouse U87MG xenograft model. MATERIALS AND METHODS: In vivo single-voxel MR spectra at 7T from xenograft tumors were obtained using both a water-suppressed and a nonwater-suppressed point-resolved spectroscopy (PRESS) sequence. Reproducibility of the total choline/water ratio was evaluated under the conditions of immediate rescan with no change in position of the animal or voxel, immediate reposition, and reposition after 1 or 7 days. RESULTS: Total choline-to-water ratios in U87MG tumor xenografts averaged ≈0.018 across all of the groups. The average percent difference between the two scans in each condition was always less than ≈3.0%, and the coefficient of variation was always less than ≈12%. Bias was unrelated to the testing condition and relatively negligible in magnitude (<3%). Due to heteroscedasticity in the ratios, the limits of agreement were calculated after log transformation of the data and ranged from ≈12% when animals were maintained in the same position and immediately rescanned to ≈52% when the two scans were 7 days apart. CONCLUSION: The total choline-to-water ratio provides a reproducible measure of choline-containing metabolites in subcutaneous U87MG xenograft tumors in mice.


Asunto(s)
Biomarcadores de Tumor/análisis , Agua Corporal/química , Colina/análisis , Glioblastoma/metabolismo , Imagen por Resonancia Magnética/métodos , Agua/análisis , Animales , Línea Celular Tumoral , Glioblastoma/diagnóstico , Humanos , Ratones , Protones , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
8.
Cancers (Basel) ; 14(15)2022 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-35892870

RESUMEN

Despite improved therapeutic and clinical outcomes for patients with localized diseases, outcomes for pediatric and AYA sarcoma patients with high-grade or aggressive disease are still relatively poor. With advancements in next generation sequencing (NGS), precision medicine now provides a strategy to improve outcomes in patients with aggressive disease by identifying biomarkers of therapeutic sensitivity or resistance. The integration of NGS into clinical decision making not only increases the accuracy of diagnosis and prognosis, but also has the potential to identify effective and less toxic therapies for pediatric and AYA sarcomas. Genome and transcriptome profiling have detected dysregulation of the CDK4/6 cell cycle regulatory pathway in subpopulations of pediatric and AYA OS, RMS, and EWS. In these patients, the inhibition of CDK4/6 represents a promising precision medicine-guided therapy. There is a critical need, however, to identify novel and promising combination therapies to fight the development of resistance to CDK4/6 inhibition. In this review, we offer rationale and perspective on the promise and challenges of this therapeutic approach.

9.
Cancers (Basel) ; 15(1)2022 Dec 30.
Artículo en Inglés | MEDLINE | ID: mdl-36612255

RESUMEN

Establishment of clinically annotated, molecularly characterized, patient-derived xenografts (PDXs) from treatment-naïve and pretreated patients provides a platform to test precision genomics-guided therapies. An integrated multi-OMICS pipeline was developed to identify cancer-associated pathways and evaluate stability of molecular signatures in a panel of pediatric and AYA PDXs following serial passaging in mice. Original solid tumor samples and their corresponding PDXs were evaluated by whole-genome sequencing, RNA-seq, immunoblotting, pathway enrichment analyses, and the drug−gene interaction database to identify as well as cross-validate actionable targets in patients with sarcomas or Wilms tumors. While some divergence between original tumor and the respective PDX was evident, majority of alterations were not functionally impactful, and oncogenic pathway activation was maintained following serial passaging. CDK4/6 and BETs were prioritized as biomarkers of therapeutic response in osteosarcoma PDXs with pertinent molecular signatures. Inhibition of CDK4/6 or BETs decreased osteosarcoma PDX growth (two-way ANOVA, p < 0.05) confirming mechanistic involvement in growth. Linking patient treatment history with molecular and efficacy data in PDX will provide a strong rationale for targeted therapy and improve our understanding of which therapy is most beneficial in patients at diagnosis and in those already exposed to therapy.

10.
Cancers (Basel) ; 12(9)2020 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-32859084

RESUMEN

Osteosarcoma (OS) patients exhibit poor overall survival, partly due to copy number variations (CNVs) resulting in dysregulated gene expression and therapeutic resistance. To identify actionable prognostic signatures of poor overall survival, we employed a systems biology approach using public databases to integrate CNVs, gene expression, and survival outcomes in pediatric, adolescent, and young adult OS patients. Chromosome 8 was a hotspot for poor prognostic signatures. The MYC-RAD21 copy number gain (8q24) correlated with increased gene expression and poor overall survival in 90% of the patients (n = 85). MYC and RAD21 play a role in replication-stress, which is a therapeutically actionable network. We prioritized replication-stress regulators, bromodomain and extra-terminal proteins (BETs), and CHK1, in order to test the hypothesis that the inhibition of BET + CHK1 in MYC-RAD21+ pediatric OS models would be efficacious and safe. We demonstrate that MYC-RAD21+ pediatric OS cell lines were sensitive to the inhibition of BET (BETi) and CHK1 (CHK1i) at clinically achievable concentrations. While the potentiation of CHK1i-mediated effects by BETi was BET-BRD4-dependent, MYC expression was BET-BRD4-independent. In MYC-RAD21+ pediatric OS xenografts, BETi + CHK1i significantly decreased tumor growth, increased survival, and was well tolerated. Therefore, targeting replication stress is a promising strategy to pursue as a therapeutic option for this devastating disease.

11.
Cell Chem Biol ; 26(3): 378-389.e13, 2019 03 21.
Artículo en Inglés | MEDLINE | ID: mdl-30581134

RESUMEN

The Hippo pathway coordinates extracellular signals onto the control of tissue homeostasis and organ size. Hippo signaling primarily regulates the ability of Yap1 to bind and co-activate TEA domain (TEAD) transcription factors. Yap1 tightly binds to TEAD4 via a large flat interface, making the development of small-molecule orthosteric inhibitors highly challenging. Here, we report small-molecule TEAD⋅Yap inhibitors that rapidly and selectively form a covalent bond with a conserved cysteine located within the unique deep hydrophobic palmitate-binding pocket of TEADs. Inhibition of TEAD4 binding to Yap1 by these compounds was irreversible and occurred on a longer time scale. In mammalian cells, the compounds formed a covalent complex with TEAD4, inhibited its binding to Yap1, blocked its transcriptional activity, and suppressed expression of connective tissue growth factor. The compounds inhibited cell viability of patient-derived glioblastoma spheroids, making them suitable as chemical probes to explore Hippo signaling in cancer.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Cisteína/química , Proteínas de Unión al ADN/metabolismo , Proteínas Musculares/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Factores de Transcripción/metabolismo , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Regulación Alostérica/efectos de los fármacos , Sitios de Unión , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Factor de Crecimiento del Tejido Conjuntivo/genética , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Proteínas de Unión al ADN/antagonistas & inhibidores , Humanos , Simulación de Dinámica Molecular , Proteínas Musculares/antagonistas & inhibidores , Dominios y Motivos de Interacción de Proteínas , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Esferoides Celulares/efectos de los fármacos , Esferoides Celulares/metabolismo , Factores de Transcripción de Dominio TEA , Termodinámica , Factores de Transcripción/antagonistas & inhibidores , Proteínas Señalizadoras YAP
12.
Neuropharmacology ; 55(5): 743-54, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18602930

RESUMEN

Selective inhibitors of the glycine transporter 1 (GlyT1) have been implicated in central nervous system disorders related to hypoglutamatergic function such as schizophrenia. The selective GlyT1 inhibitors ALX5407 (NFPS) and LY2365109 {[2-(4-benzo[1,3]dioxol-5-yl-2-tert-butylphenoxy)ethyl]-methylamino}-acetic acid increased cerebrospinal fluid levels of glycine and potentiated NMDA-induced increases in dialysate levels of neurotransmitters in the prefrontal cortex (PFC) and the striatum. However, higher doses produced both stimulatory and inhibitory effects on motor performance and impaired respiration, suggesting significant involvement of cerebellar and brain stem areas. A dual probe microdialysis study showed that ALX5407 transiently elevated extracellular levels of glycine in the PFC with more sustained increases in the cerebellum. In support of these findings, immuno-staining with pan-GlyT1 and GlyT1a antibodies showed a higher abundance of immunoreactivity in the brain stem/cerebellum as compared to the frontal cortical/hippocampal brain areas in four different species studied, including the mouse, rat, monkey and human. In addition, the inhibitory effects of ALX5407 on cerebellar levels of cGMP in the mouse could be reversed by the glycine A receptor antagonist strychnine but not the glycine B receptor antagonist L-701324. We propose that the adverse events seen with higher doses of ALX5407 and LY2365109 are the result of high GlyT1 inhibitory activity in caudal areas of the brain with sustained elevations of extracellular glycine. High levels of glycine in these brain areas may result in activation of strychnine-sensitive glycine A receptors that are inhibitory on both motor activity and critical brain stem functions such as respiration.


Asunto(s)
Conducta Animal/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Sarcosina/análogos & derivados , Animales , Línea Celular Tumoral , GMP Cíclico/metabolismo , Dioxoles/farmacología , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/farmacología , Glicina/metabolismo , Humanos , Masculino , Ratones , Microdiálisis/métodos , Actividad Motora/efectos de los fármacos , Neuroblastoma , Neurotransmisores/metabolismo , Quinolonas/farmacología , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Sarcosina/farmacología , Factores de Tiempo
13.
Neuropharmacology ; 53(8): 930-41, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17959202

RESUMEN

In humans, kappa opioid receptor agonists produce, among other effects, sedation and difficulty concentrating, suggesting that they may disrupt attention. The purpose of the present studies was therefore to evaluate the effects of kappa opioid receptor agonists on attention as assessed by a 5-choice serial reaction time task in rats. The kappa opioid receptor agonists (+)-U69,593 (0.1-0.56mg/kg), (+/-)-U50,488 (1.0-5.6mg/kg) and racemic GR89,696 (0.0003-0.01mg/kg) all produced dose-related decreases in the percentage of trials terminated by a correct or incorrect response and increases in the percentage of omissions. In contrast, the peripherally restricted opioid agonist ICI-204,448 was ineffective (1.0-10mg/kg). Moreover, the effects of GR89,696 were stereoselective in that (R)-GR89,696 was approximately equipotent to racemic GR89,696 and approximately 100-fold more potent than (S)-GR89,696. The opioid receptor antagonist naltrexone (0.3-3mg/kg) administered alone had no effects on performance. However, naltrexone, over the dose-range of 0.03-1.0mg/kg, produced a dose-related antagonism of the disruption produced by U69,593 (0.56mg/kg). In contrast, naltrexone, over the dose-range of 0.01-0.3mg/kg produced a dose-related antagonism of morphine (5.6mg/kg). Recent evidence has suggested that kappa opioid receptor agonists decrease dopaminergic and noradrenergic neurotransmission in prefrontal cortex and locus coeruleus. Together with previous findings, the present data indicate that kappa opioid receptor agonists disrupt performance of this attention task by decreasing the probability of responding by specific actions at central kappa opioid receptors, perhaps by decreasing dopaminergic and noradrenergic neurotransmission.


Asunto(s)
Analgésicos/farmacología , Atención/efectos de los fármacos , Conducta de Elección/efectos de los fármacos , Tiempo de Reacción/efectos de los fármacos , Receptores Opioides kappa/agonistas , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Masculino , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Estimulación Luminosa , Ratas , Ratas Sprague-Dawley , Receptores Opioides kappa/metabolismo
14.
Eur J Pain ; 11(2): 208-15, 2007 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-16542861

RESUMEN

OBJECTIVES: The present study was undertaken to characterize whether the pharmacologic interaction between duloxetine, a balanced serotonergic and noradrenergic reuptake inhibitor, and the non-steroidal anti-inflammatory drug ibuprofen was simply additive, less than additive, or greater than additive (i.e., synergistic) in preclinical models of visceral and inflammatory pain, specifically acetic acid-induced writhing in mice and carrageenan-induced thermal hyperalgesia and mechanical allodynia in rats. METHODS: In the writhing test, male CF-1 mice were injected intraperitoneally with 0.55% acetic acid and 5 min later the number of writhes was counted over a 5-min period. In the carrageenan models, male Sprague-Dawley rats were injected with a 1.5% carrageenan solution into the ventral surface of the hind paw; hypersensitivity to thermal and mechanical stimuli was subsequently evaluated 2h post-carrageenan. RESULTS: Vehicle or a dose of duloxetine alone (1-100 mg/kg), ibuprofen alone (10-300 mg/kg), or duloxetine and ibuprofen in combination in a dose-ratio of 1:10 duloxetine:ibuprofen were orally administered 30 or 60 min before testing. Isobolographic analysis of the effects of duloxetine in combination with ibuprofen revealed a significant synergistic (greater than additive) interaction between duloxetine and ibuprofen both for reducing acetic acid-induced writhing and carrageenan-induced thermal hyperalgesia, but were additive for reversing mechanical allodynia. CONCLUSIONS: Our data indicate that duloxetine and ibuprofen have synergistic efficacy in a visceral and an inflammatory pain model in rodents, and suggest that duloxetine and ibuprofen in combination may provide a useful approach to the clinical treatment of persistent pain, particularly inflammation-related pain.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Ibuprofeno/farmacología , Inflamación/complicaciones , Dolor/tratamiento farmacológico , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Tiofenos/farmacología , Ácido Acético , Inhibidores de Captación Adrenérgica/farmacología , Animales , Conducta Animal/efectos de los fármacos , Carragenina , Sinergismo Farmacológico , Clorhidrato de Duloxetina , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Inflamación/inducido químicamente , Masculino , Ratones , Ratones Endogámicos , Norepinefrina/metabolismo , Dolor/etiología , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismo
15.
Epilepsy Res ; 75(1): 39-45, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17485199

RESUMEN

The localization of serotonin-7 (5-HT(7)) receptors and the biological activity of ligands have suggested that 5-HT(7) receptors might be involved in pain, migraine, epilepsy, anxiety, depression, memory, and sleep. In the present study, the potential involvement of 5-HT(7) receptors in epilepsy and other seizure disorders was assessed by comparing the seizures produced by three types of electrical stimulation and three chemical convulsants in 5-HT(7) receptor-deficient (knockout, KO) mice to those seizures observed in wild-type (WT) mice. Thresholds for producing electroshock-induced clonic seizures did not differ between KO versus WT mice. However, thresholds for producing electroshock-induced tonic seizures were significantly lower in KO than in WT mice. Seizures produced by pentylenetetrazole (PTZ, a GABA(A) receptor antagonist), N-methyl-d-aspartate (NMDA, an agonist at NMDA-type glutamate receptors), and cocaine (an inhibitor of monoamine uptake) were also studied. PTZ was more potent in inducing seizures in 5-HT(7) KO mice than in wild-type mice. Likewise, cocaine was more potent in inducing seizures in 5-HT(7) KO than in WT mice; moreover, death resulted from cocaine administration in 5-HT(7) KO mice but not in WT mice. There was a similar trend for NMDA that did not reach statistical significance. The present findings point to the potential for a generalized reduction in seizure threshold with constitutive deletion of the 5-HT(7) receptor gene. Since seizures have not been reported with pharmacological blockade of the receptor, the findings suggest that adaptive changes may play a role in the low seizure thresholds in these mice. In addition, the data suggest that the lower thresholds for seizures produced by diverse mechanisms should be taken into account when interpreting other aspects of the phenotype and behavioral pharmacology of this mouse.


Asunto(s)
Convulsivantes/toxicidad , Electrochoque/efectos adversos , Eliminación de Gen , Receptores de Serotonina/genética , Convulsiones , Análisis de Varianza , Animales , Relación Dosis-Respuesta a Droga , Ratones , Ratones Noqueados , Receptores de Serotonina/deficiencia , Convulsiones/etiología , Convulsiones/genética , Convulsiones/fisiopatología
16.
Epilepsy Behav ; 10(1): 16-25, 2007 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-17174158

RESUMEN

Patients with epilepsy can have impaired cognitive abilities. Antiepileptic drugs (AEDs) may contribute to the cognitive deficits observed in patients with epilepsy, and have been shown to induce cognitive impairments in healthy individuals. However, there are few systematic data on the effects of AEDs on specific cognitive domains. We have previously demonstrated that a number of AEDs can impair working memory and attention. The purpose of the present study was to evaluate the effects of AEDs on learning as measured by a repeated acquisition of response sequences task in nonepileptic rats. The GABA-related AEDs phenobarbital and chlordiazepoxide significantly disrupted performance by shifting the learning curve to the right and increasing errors, whereas tiagabine and valproate did not. The sodium channel blockers carbamazepine and phenytoin suppressed responding at higher doses, whereas lamotrigine shifted the learning curve to the right and increased errors, and topiramate was without significant effect. Levetiracetam also shifted the learning curve to the right and increased errors. The disruptions produced by triazolam, chlordiazepoxide, lamotrigine, and levetiracetam were qualitatively similar to the effects of the muscarinic cholinergic receptor antagonist scopolamine. The present results indicate that AEDs can impair learning, but there are differences among AEDs in the magnitude of the disruption in nonepileptic rats, with drugs that enhance GABA receptor function and some that block sodium channels producing the most consistent impairment of learning.


Asunto(s)
Anticonvulsivantes/farmacología , Aprendizaje Seriado/efectos de los fármacos , Análisis de Varianza , Animales , Anticonvulsivantes/clasificación , Conducta Animal/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Interacciones Farmacológicas , Masculino , Antagonistas Muscarínicos/farmacología , Ratas , Ratas Sprague-Dawley , Refuerzo en Psicología , Escopolamina/farmacología
17.
J Neurosurg ; 126(2): 446-459, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27177180

RESUMEN

OBJECTIVE Improvement in treatment outcome for patients with glioblastoma multiforme (GBM) requires a multifaceted approach due to dysregulation of numerous signaling pathways. The murine double minute 2 (MDM2) protein may fulfill this requirement because it is involved in the regulation of growth, survival, and invasion. The objective of this study was to investigate the impact of modulating MDM2 function in combination with front-line temozolomide (TMZ) therapy in GBM. METHODS The combination of TMZ with the MDM2 protein-protein interaction inhibitor nutlin3a was evaluated for effects on cell growth, p53 pathway activation, expression of DNA repair proteins, and invasive properties. In vivo efficacy was assessed in xenograft models of human GBM. RESULTS In combination, TMZ/nutlin3a was additive to synergistic in decreasing growth of wild-type p53 GBM cells. Pharmacodynamic studies demonstrated that inhibition of cell growth following exposure to TMZ/nutlin3a correlated with: 1) activation of the p53 pathway, 2) downregulation of DNA repair proteins, 3) persistence of DNA damage, and 4) decreased invasion. Pharmacokinetic studies indicated that nutlin3a was detected in human intracranial tumor xenografts. To assess therapeutic potential, efficacy studies were conducted in a xenograft model of intracranial GBM by using GBM cells derived from a recurrent wild-type p53 GBM that is highly TMZ resistant (GBM10). Three 5-day cycles of TMZ/nutlin3a resulted in a significant increase in the survival of mice with GBM10 intracranial tumors compared with single-agent therapy. CONCLUSIONS Modulation of MDM2/p53-associated signaling pathways is a novel approach for decreasing TMZ resistance in GBM. To the authors' knowledge, this is the first study in a humanized intracranial patient-derived xenograft model to demonstrate the efficacy of combining front-line TMZ therapy and an inhibitor of MDM2 protein-protein interactions.


Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Imidazoles/uso terapéutico , Piperazinas/uso terapéutico , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Temozolomida/uso terapéutico , Animales , Neoplasias Encefálicas/patología , Terapia Combinada , Modelos Animales de Enfermedad , Glioblastoma/patología , Humanos , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Neuropharmacology ; 51(7-8): 1172-80, 2006 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17045620

RESUMEN

The efficacy of antidepressant drugs with serotonergic, noradrenergic, or dual reuptake inhibition was evaluated in reversing carrageenan-induced thermal hyperalgesia and mechanical allodynia in rats. Duloxetine (1-30mg/kg, i.p.), a balanced serotonergic-noradrenergic reuptake inhibitor (SNRI), was equiefficacious and more potent than the SNRI venlafaxine (3-100mg/kg, i.p.) in reversing both thermal hyperalgesia and mechanical allodynia induced by carrageenan. In addition, the selective noradrenergic reuptake inhibitors (NRIs) thionisoxetine (0.03-10mg/kg, i.p.) and desipramine (1-30mg/kg, i.p.) also produced complete reversals of carrageenan-induced thermal hyperalgesia. However, only thionisoxetine exhibited a greater than 80% reversal of the carrageenan-induced mechanical allodynia. In contrast, the selective serotonergic reuptake inhibitors (SSRIs) paroxetine, sertraline, and fluoxetine (0.3-10mg/kg i.p.) had little or no effect in the carrageenan model. In order to understand whether the observed enhanced effectiveness of the dual SNRIs was due to a possible synergism between serotonergic and noradrenergic reuptake inhibition, the effects of the NRI thionisoxetine alone and in combination with an inactive dose of the SSRI fluoxetine were determined. In the presence of fluoxetine, the potency of thionisoxetine in reversing carrageenan-induced hyperalgesia and allodynia was significantly increased by approximately 100-fold and brain concentrations of thionisoxetine were increased by 1.1- to 5-fold. The present data indicate fluoxetine pharmacodynamically potentiated the analgesic effects of thionisoxetine over and above a metabolic interaction between these two drugs. The present findings thus indicate that, in the carrageenan model, dual serotonergic-noradrenergic reuptake inhibition by dual SNRIs, or SSRI-NRI combinations, produces synergistic analgesic efficacy.


Asunto(s)
Inhibidores de Captación Adrenérgica/uso terapéutico , Analgésicos no Narcóticos/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Norepinefrina/fisiología , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Serotonina/fisiología , Inhibidores de Captación Adrenérgica/farmacología , Analgésicos no Narcóticos/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Química Encefálica/efectos de los fármacos , Carragenina/toxicidad , Ciclohexanoles/farmacología , Ciclohexanoles/uso terapéutico , Desipramina/farmacología , Desipramina/uso terapéutico , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Interacciones Farmacológicas , Clorhidrato de Duloxetina , Edema/inducido químicamente , Edema/tratamiento farmacológico , Fluoxetina/análogos & derivados , Fluoxetina/análisis , Fluoxetina/farmacología , Fluoxetina/uso terapéutico , Calor/efectos adversos , Hiperalgesia/inducido químicamente , Hiperalgesia/fisiopatología , Masculino , Paroxetina/farmacología , Paroxetina/uso terapéutico , Presión/efectos adversos , Ratas , Ratas Sprague-Dawley , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Sertralina/farmacología , Sertralina/uso terapéutico , Tiofenos/farmacología , Tiofenos/uso terapéutico , Clorhidrato de Venlafaxina
19.
Neuropharmacology ; 48(6): 779-87, 2005 May.
Artículo en Inglés | MEDLINE | ID: mdl-15829250

RESUMEN

The purpose of the present studies was to investigate the behavioral and convulsant effects produced by the group I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG). Administered i.c.v. to mice, (S)-3,5-DHPG produced a behavioral syndrome consisting of scratching and/or facial grooming, tremors, slow forelimb clonus, rearing, and falling that increased over the dose range of 10-400 nmol. The full syndrome, produced by 400 nmol of (S)-3,5-DHPG, was antagonized by the selective mGlu1 receptor antagonist LY456236 but not by the mGlu5 receptor antagonist MPEP or the mGlu2/3 receptor antagonist LY341495. The behaviors induced by the 400 nmol dose were not blocked by the NMDA receptor antagonist MK-801, but were attenuated by the non-NMDA receptor antagonists GYKI 52466 and NBQX, and the Ca2+ mobilization inhibitor dantrolene, but at motor-impairing doses. The scratching behaviors produced by 30 nmol of (S)-3,5-DHPG were antagonized by LY456236 but not by MPEP, LY341495 or MK-801. GYKI 52466 and dantrolene, but not NBQX, inhibited scratching at motor-impairing doses. Both 400 and 30 nmol of (S)-3,5-DHPG produced a generalized seizure as recorded by surface EEG electrodes. LY456236 blocked the seizures produced by 30 nmol but not by 400 nmol; dantrolene was ineffective in blocking seizures produced by either dose. The present findings suggest that (S)-3,5-DHPG produces an increase in excitation that is mediated by mGlu1 and non-NMDA receptors.


Asunto(s)
Conducta Animal/efectos de los fármacos , Síntomas Conductuales/fisiopatología , Convulsivantes/farmacología , Agonistas de Aminoácidos Excitadores/farmacología , Glicina/análogos & derivados , Glicina/farmacología , Resorcinoles/farmacología , Animales , Síntomas Conductuales/inducido químicamente , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Electroencefalografía/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Masculino , Ratones , Ratones Endogámicos ICR , Análisis de Regresión
20.
Neuropharmacology ; 49 Suppl 1: 188-95, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-16011839

RESUMEN

Several lines of evidence suggest that mGlu1 metabotropic glutamate receptors may be involved in seizure disorders such as epilepsy. For example, the mGlu1 agonist DHPG produces limbic seizures and group I antagonists such as 4C3HPG and 4CPG are anticonvulsant when administered intracerebrally. The purpose of the present experiments was to characterize the anticonvulsant effects of the selective mGlu1 receptor antagonist LY456236 in mice and rats. In male and female DBA/2 mice, LY456236 produced a dose-related inhibition of sound-induced clonic-tonic seizures. In male CF1 mice, LY456236 produced a dose-related inhibition of tonic extensor seizures in the threshold electroshock model, and limbic seizures in the 6-Hz focal seizure model. However, this antagonist did not inhibit clonic seizures produced by pentylenetetrazol. In amygdala-kindled male Sprague-Dawley rats, LY456236 produced dose-related decreases in behavioral and electrographic seizures at threshold stimulus intensity. In addition, LY456236 produced a dose-related increase in the stimulus intensity required to produce generalized seizures. Taken together, the present results support the conclusion that mGlu1 receptor antagonists such as LY456236 may have clinical utility in the treatment of epilepsy and other seizure disorders.


Asunto(s)
Anticonvulsivantes/uso terapéutico , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Convulsiones/tratamiento farmacológico , Estimulación Acústica/efectos adversos , Animales , Relación Dosis-Respuesta a Droga , Electrochoque/efectos adversos , Masculino , Ratones , Ratones Endogámicos DBA , Pentilenotetrazol , Quinazolinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Convulsiones/inducido químicamente , Convulsiones/etiología , Umbral Sensorial/fisiología , Factores de Tiempo
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