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1.
Mol Cancer Ther ; 10(9): 1542-52, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21764904

RESUMEN

We describe here the identification and characterization of 2 novel inhibitors of the fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases. The compounds exhibit selective inhibition of FGFR over the closely related VEGFR2 receptor in cell lines and in vivo. The pharmacologic profile of these inhibitors was defined using a panel of human tumor cell lines characterized for specific mutations, amplifications, or translocations known to activate one of the four FGFR receptor isoforms. This pharmacology defines a profile for inhibitors that are likely to be of use in clinical settings in disease types where FGFR is shown to play an important role.


Asunto(s)
Antineoplásicos/farmacología , Factores de Crecimiento de Fibroblastos/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Animales , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores de Factores de Crecimiento de Fibroblastos/genética , Transducción de Señal/efectos de los fármacos , Resultado del Tratamiento , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Br J Haematol ; 149(4): 529-36, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-20331455

RESUMEN

Pharmacological inhibitors of histone deacetylases (HDACs) are currently being developed and tested as anti-cancer agents and may be useful to enhance the therapeutic efficiency of established anti-myeloma treatments. This study preclinically evaluated the effects of the 'second generation' pan-HDAC inhibitor JNJ-26481585 on human multiple myeloma (MM) cells from established cell lines and primary MM samples (n=42). Molecular responses in both groups of MM cells included histone acetylation, a shift in Bcl2-family members towards proapoptotic bias, attenuation of growth and survival pathway activity and Hsp72 induction. Mcl-1 depletion and Hsp72 induction were the most reliable features observed in JNJ-26481585-treated primary MM samples. The drug alone effectively induced myeloma cell death at low nanomolar concentrations. In vitro combination of JNJ-26481585 with anti-myeloma therapeutic agents generally resulted In effects close to additivity. In view of the favourable activity of this novel HDAC-inhibitor towards primary myeloma cells further evaluation in a clinical setting is warranted.


Asunto(s)
Antineoplásicos/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Mieloma Múltiple/patología , Acetilación/efectos de los fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Histonas/metabolismo , Humanos , Mieloma Múltiple/metabolismo , Células Tumorales Cultivadas
3.
Mol Cancer Ther ; 8(7): 1846-55, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19584230

RESUMEN

Multitargeted kinase inhibitors have shown clinical efficacy in a range of cancer types. However, two major problems associated with these drugs are the low fraction of patients for which these treatments provide initial clinical benefit and the occurrence of resistance during prolonged therapy. Several types of predictive biomarkers have been suggested, such as expression level and phosphorylation status of the major targeted kinase(s), mutational status of the kinases involved and of key components of the downstream signaling cascades, and gene expression signatures. In this work, we describe the development of a response prediction platform that does not require prior knowledge of the relevant kinases targeted by the inhibitor; instead, a phosphotyrosine peptide profile using peptide arrays with a kinetic readout is derived in lysates in the presence and absence of a kinase inhibitor. We show in a range of cell lines and in xenograft tumors that this approach allows for the stratification of responders and nonresponders to a multitargeted kinase inhibitor.


Asunto(s)
Neoplasias/tratamiento farmacológico , Análisis por Matrices de Proteínas , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/metabolismo , Tirosina/metabolismo , Animales , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Perfilación de la Expresión Génica , Humanos , Cinética , Ratones , Ratones Desnudos , Neoplasias/metabolismo , Neoplasias/patología , Fosforilación , Fosfotirosina/metabolismo , Proteínas Tirosina Quinasas/análisis , Trasplante Heterólogo
4.
Curr Drug Targets ; 6(2): 225-40, 2005 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-15777192

RESUMEN

Obesity, a condition already at epidemic proportions in the developed world, is largely attributable to an indulgent lifestyle. Biologically we feel hunger more acutely than feeling "full-up" (satiety). The discovery over a decade ago of leptin, an adiposity signal, revolutionised our understanding of hypothalamic mechanisms underpinning the central control of ingestive behaviour. The structure and function of many hypothalamic peptides (Neuropeptide Y (NPY), Melanocortins, Agouti related peptide (AGRP), Cocaine and amphetamine regulated transcript (CART), Melanin concentrating hormone (MCH), Orexins and endocannabinoids) have been characterised in rodent models. The pharmacological potential of several endogenous peripheral peptides released prior to, during and/or after feeding are being explored. Short-term signal hormones including Cholecystokinin (CCK), Ghrelin, Peptide YY (PYY(3-36)) and Glucagon-like peptide 1 (GLP-1) control meal size via pathways converging on the hypothalamus. Long-term regulation is provided by the main circulating hormones leptin and insulin. These systems among others, implicated in hypothalamic appetite regulation all provide potential "drugable" targets by which to treat obesity.


Asunto(s)
Hipotálamo/fisiología , Obesidad/fisiopatología , Animales , Encéfalo/fisiología , Metabolismo Energético/fisiología , Humanos , Sistema Nervioso Periférico/fisiología
5.
Brain Res Mol Brain Res ; 128(2): 150-9, 2004 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-15363890

RESUMEN

Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that stimulates feeding and increases body weight in rodents. We studied the role of the system in energy homeostasis and its regulation by the satiety signals, leptin and insulin. We used real-time PCR to measure the hypothalamic expression of MCH and its receptor (MCHR1) in two contrasting models of altered nutritional status, namely, obesity induced by 8 weeks' voluntary overeating and food restriction for 10 days. Diet-fed rats were stratified according to final total fat-pad mass into a 'high fat gain' group (HG) and 'low fat gain' group (LG). MCH mRNA levels were increased by 31% (p>0.05) and 49% (p<0.05) in the LG and HG, respectively, compared with controls. MCHR1 mRNA levels rose by 118% in the LG (p<0.01) and 85% in the HG (p<0.01). There were significant positive correlations (p<0.05) between plasma leptin concentration and both MCH and MCHR1 mRNA levels, and between plasma insulin and MCHR1 expression. A positive correlation was also observed between MCH and MCHR1 mRNA levels (p<0.05). Food-restricted rats showed no significant alterations in the levels of either MCH mRNA or MCHR1 mRNA. In a second experiment, we measured MCH peptide levels in five discrete hypothalamic areas of dietary-obese rats. MCH concentrations were significantly increased in the arcuate nuclei of the HG (p<0.05) and the paraventricular nuclei of both the LG (p<0.05) and HG (p<0.05), compared with their lean counterparts. These results suggest that the MCH system becomes more active in dietary obesity and could be involved in enhancing appetite for palatable food. The possibility that MCH and MCHR1 expression are positively regulated by leptin and insulin, which normally inhibit feeding, is a putative explanation for how appetite for palatable food is able to override mechanisms that prevent the development of obesity.


Asunto(s)
Dieta/efectos adversos , Hormonas Hipotalámicas/metabolismo , Hipotálamo/metabolismo , Melaninas/metabolismo , Obesidad/metabolismo , Hormonas Hipofisarias/metabolismo , Receptores de la Hormona Hipofisaria/metabolismo , Animales , Glucemia , Índice de Masa Corporal , Peso Corporal , Hormonas Hipotalámicas/genética , Insulina/sangre , Leptina/sangre , Masculino , Melaninas/genética , Obesidad/inducido químicamente , Hormonas Hipofisarias/genética , ARN Mensajero/biosíntesis , Radioinmunoensayo/métodos , Ratas , Receptores de la Hormona Hipofisaria/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos
6.
Brain Res ; 952(2): 232-8, 2002 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-12376184

RESUMEN

Agonists at cannabinoid-1 (CB-1) receptors stimulate feeding and particularly enhance the reward aspects of eating. To investigate whether endogenous cannabinoids might influence appetite for palatable food, we compared CB-1 receptor density in the forebrain and hypothalamus, between rats fed standard chow (n=8) and others given palatable food (n=8) for 10 weeks to induce dietary obesity. CB-1 receptor density was significantly decreased by 30-50% (P<0.05) in the hippocampus, cortex, nucleus accumbens and entopeduncular nucleus of diet-fed rats. Furthermore, CB-1 receptor density in the hippocampus, nucleus accumbens and entopeduncular nucleus was significantly inversely correlated with intake of palatable food (r(2)=0.25-0.35; all P<0.05). By contrast, CB-1 receptor binding in the hypothalamus was low and not altered in diet-fed rats. CB-1 receptor down-regulation is consistent with increased activation of these receptors by endogenous cannabinoids. Acting in areas such as the nucleus accumbens and hippocampus, which are involved in the hedonic aspects of eating, cannabinoids may therefore drive appetite for palatable food and thus determine total energy intake and the severity of diet-induced obesity. However, cannabinoids in the hypothalamus do not appear to influence this aspect of eating behaviour.


Asunto(s)
Apetito/fisiología , Regulación hacia Abajo/fisiología , Ácidos Grasos Insaturados/fisiología , Hipotálamo/metabolismo , Obesidad/metabolismo , Receptores de Droga/antagonistas & inhibidores , Receptores de Droga/biosíntesis , Animales , Regulación del Apetito/fisiología , Moduladores de Receptores de Cannabinoides , Ingestión de Energía/fisiología , Masculino , Ratas , Ratas Wistar , Receptores de Cannabinoides
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