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1.
Front Endocrinol (Lausanne) ; 12: 712107, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34475850

RESUMEN

Background: Treatment options for poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising. Materials and Methods: Primary ATC (n=93) and PDTC (n=47) tissue samples diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1 expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4 mRNA was quantified in 31 ATC and 14 PDTC with RNAscope in-situ hybridization. Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls. Disease specific survival (DSS) was the primary outcome variable. Results: PD-L1 TPS≥50% was observed in 42% of ATC and 26% of PDTC specimens. Mean PD-L1 expression was significantly higher in ATC (TPS 30%) than in PDTC (5%; p<0.01) and NT (0%, p<0.001). 53% of PDTC samples had PD-L1 expression ≤5%. FGFR mRNA expression was generally low in all samples but combined FGFR1-4 expression was significantly higher in PDTC and ATC compared to NT (each p<0.001). No impact of PD-L1 and FGFR 1-4 expression was observed on DSS. Conclusion: High tumoral expression of PD-L1 in a large proportion of ATCs and a subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR expression is low thyroid tumor cells. The clinically observed synergism of PEM with LEN may be caused by immune modulation.


Asunto(s)
Antígeno B7-H1/antagonistas & inhibidores , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/farmacología , Antineoplásicos , Antineoplásicos Inmunológicos , Antígeno B7-H1/análisis , Evaluación Preclínica de Medicamentos/métodos , Femenino , Alemania , Humanos , Masculino , Persona de Mediana Edad , Compuestos de Fenilurea/farmacología , Quinolinas/farmacología , ARN Mensajero/análisis , Receptores de Factores de Crecimiento de Fibroblastos/genética , Carcinoma Anaplásico de Tiroides/química , Carcinoma Anaplásico de Tiroides/patología , Neoplasias de la Tiroides/química , Neoplasias de la Tiroides/patología
2.
Pharmacol Res Perspect ; 9(2): e00759, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33811484

RESUMEN

Endometriosis is a chronic disease, characterized by the growth of endometrial-like cells outside the uterine cavity. Due to its complex pathophysiology, a totally resolving cure is yet to be found. The aim of this study was to compare the therapeutic efficacy of AZD4547, a novel fibroblast growth factor receptor inhibitor (FGFRI), with a well-characterized progestin, etonogestrel (ENG) using a validated in vivo mouse model of endometriosis. Endometriosis was induced by transplanting uterine fragments from donor mice in proestrus into the peritoneal cavity of recipient mice, which then developed into cyst-like lesions. AZD4547 and ENG were administered systemically either from the day of endometriosis induction or 2-weeks post-surgery. After 20 days of treatment, the lesions were harvested; their size and weight were measured and analyzed histologically or by qRT-PCR. Stage of estrous cycle was monitored throughout. Compared to vehicle, AZD4547 (25 mg/kg) was most effective in counteracting lesion growth when treating from day of surgery and 2 weeks after; ENG (0.8 mg/kg) was similarly effective in reducing lesion growth but only when administered from day of surgery. Each downregulated FGFR gene expression (p < 0.05). AZD4547 at all doses and ENG (0.008 mg/kg) caused no disturbance to the estrous cycle. ENG at 0.08 and 0.8 mg/kg was associated with partial or complete estrous cycle disruption and hyperemia of the uteri. AZD4547 and ENG both attenuated endometriotic lesion size, but only AZD4547 did not disrupt the estrous cycle, suggesting that targeting of FGFR is worthy of further investigation as a novel treatment for endometriosis.


Asunto(s)
Benzamidas/administración & dosificación , Endometriosis/tratamiento farmacológico , Ciclo Estral/efectos de los fármacos , Piperazinas/administración & dosificación , Pirazoles/administración & dosificación , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Animales , Benzamidas/efectos adversos , Desogestrel/administración & dosificación , Desogestrel/efectos adversos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Endometriosis/patología , Endometrio/efectos de los fármacos , Endometrio/patología , Femenino , Humanos , Ratones , Piperazinas/efectos adversos , Pirazoles/efectos adversos , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo
3.
Aging (Albany NY) ; 11(18): 7780-7795, 2019 09 23.
Artículo en Inglés | MEDLINE | ID: mdl-31545294

RESUMEN

Rapid appearance of resistance to fibroblast growth factor receptor (FGFR) inhibitors hampers targeted regimens in bladder cancer. In the present study, we evaluated whether SIP-SII, a sulphated derivative of the polysaccharide in Sepiella maindroni (spineless cuttlefish) ink used in traditional Chinese medicine, could attenuate resistance to FGFR inhibition in bladder cancer cells. In vitro assays indicated that SIP-SII reduced cell viability and migration, restricted cell cycle progression, and increased apoptosis in parallel with decreased AKT phosphorylation and downregulation of CDK4, MMP2, and Bcl-2 in RT112 and JMSU1 cells. Synergistic effects on cell viability were observed when SIP-SII was combined with the small-molecule FGFR inhibitor AZD4547. Specific Akt targeting by SIP-SII was suggested by the fact that neither Akt knockdown nor the selective PI3K inhibitor BKM120 enhanced the inhibitory effects of SIP-II, while expression of a constitutively active Akt mutant rescued SIP-SII effects. Furthermore, subcutaneous transplantation of RT112 xenografts confirmed the superiority and tolerability of combined SIP-SII and AZD4547 administration over monotherapy regimens. The present study thus provides pre-clinical evidence of the ability of SIP-SII to improve FGFR-targeted therapies for bladder cancer by inhibiting Akt.


Asunto(s)
Antineoplásicos/farmacología , Benzamidas/farmacología , Decapodiformes , Resistencia a Antineoplásicos/efectos de los fármacos , Piperazinas/farmacología , Polisacáridos/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirazoles/farmacología , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Tinta , Fosforilación/efectos de los fármacos , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Neoplasias de la Vejiga Urinaria/metabolismo
4.
Cell Death Dis ; 9(3): 262, 2018 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-29449529

RESUMEN

Erlotinib resistance causes a high degree of lethality in non-small-cell lung cancer (NSCLC) patients. The high expression and activation of several receptor tyrosine kinases, such as JAK/STAT3, c-Met, and EGFR, play important roles in drug resistance. The development of tyrosine kinase inhibitors is urgently required in the clinic. Our previous study found that Gambogenic acid (GNA), a small molecule derived from the traditional Chinese medicine herb gamboge, induced cell death in several NSCLC cell lines through JAK/STAT3 inhibition. In this study, we investigated the mechanism of action of GNA in erlotinib-resistant NSCLC and patient-derived cells. The inhibition of GNA on FGFR signaling pathway was examined using biochemical kinase assays. NSCLC cell lines (HCC827, HCC827-Erlotinib-resistant, and H1650) and primary cells from patients with NSCLC with clinical resistance to erlotinib were treated with GNA, erlotinib, or their combination. Both kinase assays and cell- based assays showed that GNA inhibits the phosphorylation of multiple kinases in FGFR signaling pathway in NSCLC. The combination of GNA and erlotinib significantly attenuates the tumor growth of HCC827 and erlotinib-resistant HCC827 xenografts with low toxicity. Importantly, GNA significantly suppresses tumor growth in a lung patient-derived xenograft (PDX) model with FGFR fusion and low EGFR expression. Our findings provide preclinical evidence for using GNA as an FGFR signaling pathway inhibitor to overcome erlotinib resistance in NSCLC treatment or to enhance erlotinib efficacy when used as a combined administration.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Resistencia a Antineoplásicos , Clorhidrato de Erlotinib/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Xantenos/farmacología , Animales , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Sinergismo Farmacológico , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Femenino , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Ratones Endogámicos BALB C , Ratones Desnudos , Fosforilación , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Transducción de Señal , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
5.
Clin Cancer Res ; 24(5): 1176-1189, 2018 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-29222162

RESUMEN

Purpose: MPT0L145 has been developed as a FGFR inhibitor exhibiting significant anti-bladder cancer activity in vitro and in vivo via promoting autophagy-dependent cell death. Here, we aim to elucidate the underlying mechanisms.Experimental Design: Autophagy flux, morphology, and intracellular organelles were evaluated by Western blotting, transmission electron microscope, and fluorescence microscope. Molecular docking and surface plasmon resonance assay were performed to identify drug-protein interaction. Lentiviral delivery of cDNA or shRNA and CRISPR/Cas9-mediated genome editing was used to modulate gene expression. Mitochondrial oxygen consumption rate was measured by a Seahorse XFe24 extracellular flux analyzer, and ROS level was measured by flow cytometry.Results: MPT0L145 persistently increased incomplete autophagy and phase-lucent vacuoles at the perinuclear region, which were identified as enlarged and alkalinized late-endosomes. Screening of a panel of lipid kinases revealed that MPT0L145 strongly inhibits PIK3C3 with a Kd value of 0.53 nmol/L. Ectopic expression of PIK3C3 reversed MPT0L145-increased cell death and incomplete autophagy. Four residues (Y670, F684, I760, D761) at the ATP-binding site of PIK3C3 are important for the binding of MPT0L145. In addition, MPT0L145 promotes mitochondrial dysfunction, ROS production, and DNA damage, which may in part, contribute to cell death. ATG5-knockout rescued MPT0L145-induced cell death, suggesting simultaneous induction of autophagy is crucial to its anticancer activity. Finally, our data demonstrated that MPT0L145 is able to overcome cisplatin resistance in bladder cancer cells.Conclusions: MPT0L145 is a first-in-class PIK3C3/FGFR inhibitor, providing an innovative strategy to design new compounds that increase autophagy, but simultaneously perturb its process to promote bladder cancer cell death. Clin Cancer Res; 24(5); 1176-89. ©2017 AACR.


Asunto(s)
Autofagia/efectos de los fármacos , Fosfatidilinositol 3-Quinasas Clase III/antagonistas & inhibidores , Compuestos de Fenilurea/farmacología , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Triazinas/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Autofagia/genética , Proteína 5 Relacionada con la Autofagia/genética , Proteína 5 Relacionada con la Autofagia/metabolismo , Línea Celular Tumoral , Cisplatino/farmacología , Cisplatino/uso terapéutico , Fosfatidilinositol 3-Quinasas Clase III/metabolismo , Evaluación Preclínica de Medicamentos , Resistencia a Antineoplásicos/efectos de los fármacos , Técnicas de Inactivación de Genes , Humanos , Simulación del Acoplamiento Molecular , Compuestos de Fenilurea/uso terapéutico , Unión Proteica , Pirimidinas/farmacología , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Triazinas/uso terapéutico , Neoplasias de la Vejiga Urinaria/patología
6.
Toxicol Pathol ; 45(7): 869-875, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28643552

RESUMEN

Most toxic physeal changes are characterized microscopically by altered chondrocyte development, proliferation, or maturation in the growth plate and eventually result in disordered appositional bone growth. Many therapeutic drugs directly or indirectly target proteins involved in chondrocytic differentiation and maturation pathways, so toxic physeal injury has become increasingly common in preclinical toxicologic pathology. While physeal dysplasia has been associated with several different drug classes including bisphosphonates, vascular endothelial growth factor receptor inhibitors, fibroblast growth factor receptor inhibitors, transforming growth factor beta receptor inhibitors, and vascular targeting agents, physeal changes often share similar morphologic features including thickening and disorganization of the hypertrophic layer, increased numbers of hypertrophic chondrocytes, altered mineralization of endochondral ossification, and/or increased thickness of subphyseal bone. Knowledge of genetic and nutritional diseases affecting bone growth has been important in helping to determine which specific target drugs may be affecting that could result in toxic physeal lesions. A pathophysiologic mechanism for most physeal toxicants has been determined in detail using a variety of investigative techniques. However, due to the signaling cross talk and the tight regulation required for chondrocyte maturation in the physis, several growth factor pathways are likely to be affected simultaneously with pharmacologic disruption of physeal homeostasis and inhibition of one factor necessary for chondrocyte function often affects others.


Asunto(s)
Desarrollo Óseo/efectos de los fármacos , Enfermedades Óseas/inducido químicamente , Evaluación Preclínica de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Placa de Crecimiento/efectos de los fármacos , Animales , Enfermedades Óseas/fisiopatología , Huesos/efectos de los fármacos , Huesos/fisiopatología , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Difosfonatos/efectos adversos , Modelos Animales de Enfermedad , Placa de Crecimiento/patología , Humanos , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptores de Factores de Crecimiento Transformadores beta/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores
7.
Oncogene ; 35(34): 4518-28, 2016 08 25.
Artículo en Inglés | MEDLINE | ID: mdl-26853465

RESUMEN

Mutations to fibroblast growth factor receptor 3 (FGFR3) and phosphatase and tensin homologue (PTEN) signalling pathway components (for example, PTEN loss, PIK3CA, AKT1, TSC1/2) are common in bladder cancer, yet small-molecule inhibitors of these nodes (FGFR/PTENi) show only modest activity in preclinical models. As activation of autophagy is proposed to promote survival under FGFR/PTENi, we have investigated this relationship in a panel of 18 genetically diverse bladder cell lines. We found that autophagy inhibition does not sensitise bladder cell lines to FGFR/PTENi, but newly identify an autophagy-independent cell death synergy in FGFR3-mutant cell lines between mTOR (mammalian target of rapamycin) pathway inhibitors and chloroquine (CQ)-an anti-malarial drug used as a cancer therapy adjuvant in over 30 clinical trials. The mechanism of synergy is consistent with lysosomal cell death (LCD), including cathepsin-driven caspase activation, and correlates with suppression of cSREBP1 and cholesterol biosynthesis in sensitive cell lines. Remarkably, loss of viability can be rescued by saturating cellular membranes with cholesterol or recapitulated by statin-mediated inhibition, or small interfering RNA knockdown, of enzymes regulating cholesterol metabolism. Modulation of CQ-induced cell death by atorvastatin and cholesterol is reproduced across numerous cell lines, confirming a novel and fundamental role for cholesterol biosynthesis in regulating LCD. Thus, we have catalogued the molecular events underlying cell death induced by CQ in combination with an anticancer therapeutic. Moreover, by revealing a hitherto unknown aspect of lysosomal biology under stress, we propose that suppression of cholesterol metabolism in cancer cells should elicit synergy with CQ and define a novel approach to future cancer treatments.


Asunto(s)
Cloroquina/farmacología , Colesterol/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Atorvastatina/farmacología , Autofagia , Línea Celular Tumoral , Permeabilidad de la Membrana Celular/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Lisosomas/metabolismo , Fosfohidrolasa PTEN/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/fisiología , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología
8.
Future Oncol ; 11(9): 1373-9, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25952783

RESUMEN

Successful management of advanced colorectal cancer has been a challenging job for practicing oncologists as well as a priority for the oncology research community. The better understanding of the underlying patho-biology and critical pathway targets in this disease has contributed to major developments in that direction. In this review, we will revise the different biological and clinical aspects related to the use of FGFR pathway-targeted therapies in advanced colorectal cancer with particular focus on future perspectives in that regard.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Terapia Molecular Dirigida , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Biomarcadores , Neoplasias Colorrectales/diagnóstico , Evaluación Preclínica de Medicamentos , Humanos , Imagen Molecular , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Transducción de Señal , Investigación Biomédica Traslacional
9.
Mol Cancer Ther ; 12(6): 992-1001, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23729403

RESUMEN

Signaling from other angiokinases may underlie resistance to VEGF-directed therapy. We evaluated the antitumor and biologic effects of BIBF 1120 (nintedanib), a tyrosine kinase inhibitor that targets VEGF receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor in preclinical models of lung and pancreatic cancer, including models resistant to VEGF-targeted treatments. In vitro, BIBF 1120 did not show antiproliferative effects, nor did it sensitize tumor cells to chemotherapy. However, in vivo BIBF 1120 inhibited primary tumor growth in all models as a single agent and in combination with standard chemotherapy. Analysis of tumor tissue posttreatment revealed that BIBF 1120 reduced proliferation (phospho-histone 3) and elevated apoptosis (cleaved caspase-3) to a greater extent than chemotherapy alone. Furthermore, BIBF 1120 showed potent antiangiogenic effects, including decreases in microvessel density (CD31), pericyte coverage (NG2), vessel permeability, and perfusion, while increasing hypoxia. Despite the induction of hypoxia, markers of epithelial-to-mesenchymal transition (EMT) were not elevated in BIBF 1120-treated tumors. In summary, BIBF 1120 showed potent antitumor and antiangiogenic activity in preclinical models of lung and pancreatic cancer where it induced hypoxia but not EMT. The absence of EMT induction, which has been implicated in resistance to antiangiogenic therapies, is noteworthy. Together, these results warrant further clinical studies of BIBF 1120.


Asunto(s)
Indoles/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Evaluación Preclínica de Medicamentos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Hipoxia/inducido químicamente , Neoplasias Pulmonares/patología , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/genética , Neoplasias Pancreáticas/patología , Inhibidores de Proteínas Quinasas , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Ensayos Antitumor por Modelo de Xenoinjerto
10.
Clin Cancer Res ; 19(13): 3693-702, 2013 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-23658459

RESUMEN

PURPOSE: Fibroblast growth factor receptor 1 (FGFR1) and FGFR2 amplifications are observed in approximately 10% of breast cancers and are related to poor outcomes. We evaluated whether dovitinib (TKI258), an inhibitor of FGFR1, FGFR2, and FGFR3, presented antitumor activity in FGFR-amplified breast cancers. EXPERIMENTAL DESIGN: Preclinical activity of dovitinib was evaluated in both breast cancer cell lines and an FGFR1-amplified xenograft model (HBCx2). Dovitinib was then evaluated in a phase II trial that included 4 groups of patients with human EGF receptor 2-negative metastatic breast cancer on the basis of FGFR1 amplification and hormone receptor (HR) status. FGFR1 amplification was assessed by silver in situ hybridization. Preplanned retrospective analyses assessed predictive value of FGFR1, FGFR2, and FGF3 amplifications by quantitative PCR (qPCR). RESULTS: Dovitinib monotherapy inhibits proliferation in FGFR1- and FGFR2-amplified, but not FGFR-normal, breast cancer cell lines. Dovitinib also inhibits tumor growth in FGFR1-amplified breast cancer xenografts. Eighty-one patients were enrolled in the trial. Unconfirmed response or stable disease for more than 6 months was observed in 5 (25%) and 1 (3%) patient(s) with FGFR1-amplified/HR-positive and FGFR1-nonamplified/HR-positive breast cancer. When qPCR-identified amplifications in FGFR1, FGFR2, or FGF3 were grouped to define an FGF pathway-amplified breast cancer in HR-positive patients, the mean reduction in target lesions was 21.1% compared with a 12.0% increase in patients who did not present with FGF pathway-amplified breast cancer. CONCLUSION: Dovitinib showed antitumor activity in FGFR-amplified breast cancer cell lines and may have activity in breast cancers with FGF pathway amplification.


Asunto(s)
Antineoplásicos/uso terapéutico , Bencimidazoles/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Quinolonas/uso terapéutico , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Adulto , Anciano , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Bencimidazoles/efectos adversos , Bencimidazoles/farmacología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Factor 3 de Crecimiento de Fibroblastos/genética , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Amplificación de Genes , Humanos , Ratones , Persona de Mediana Edad , Estadificación de Neoplasias , Quinolonas/efectos adversos , Quinolonas/farmacología , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Receptores de Factores de Crecimiento de Fibroblastos/genética , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Transducción de Señal/efectos de los fármacos , Resultado del Tratamiento , Ensayos Antitumor por Modelo de Xenoinjerto
11.
J Bone Miner Res ; 28(4): 899-911, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23129509

RESUMEN

Fibroblast growth factor 23 (FGF23) is a circulating factor secreted by osteocytes that is essential for phosphate homeostasis. In kidney proximal tubular cells FGF23 inhibits phosphate reabsorption and leads to decreased synthesis and enhanced catabolism of 1,25-dihydroxyvitamin D3 (1,25[OH]2 D3 ). Excess levels of FGF23 cause renal phosphate wasting and suppression of circulating 1,25(OH)2 D3 levels and are associated with several hereditary hypophosphatemic disorders with skeletal abnormalities, including X-linked hypophosphatemic rickets (XLH) and autosomal recessive hypophosphatemic rickets (ARHR). Currently, therapeutic approaches to these diseases are limited to treatment with activated vitamin D analogues and phosphate supplementation, often merely resulting in partial correction of the skeletal aberrations. In this study, we evaluate the use of FGFR inhibitors for the treatment of FGF23-mediated hypophosphatemic disorders using NVP-BGJ398, a novel selective, pan-specific FGFR inhibitor currently in Phase I clinical trials for cancer therapy. In two different hypophosphatemic mouse models, Hyp and Dmp1-null mice, resembling the human diseases XLH and ARHR, we find that pharmacological inhibition of FGFRs efficiently abrogates aberrant FGF23 signaling and normalizes the hypophosphatemic and hypocalcemic conditions of these mice. Correspondingly, long-term FGFR inhibition in Hyp mice leads to enhanced bone growth, increased mineralization, and reorganization of the disturbed growth plate structure. We therefore propose NVP-BGJ398 treatment as a novel approach for the therapy of FGF23-mediated hypophosphatemic diseases.


Asunto(s)
Factores de Crecimiento de Fibroblastos/metabolismo , Compuestos de Fenilurea/farmacología , Pirimidinas/farmacología , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Raquitismo Hipofosfatémico/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Desarrollo Óseo/efectos de los fármacos , Proteínas de la Matriz Extracelular/deficiencia , Proteínas de la Matriz Extracelular/metabolismo , Fémur/efectos de los fármacos , Fémur/patología , Factor-23 de Crecimiento de Fibroblastos , Placa de Crecimiento/efectos de los fármacos , Placa de Crecimiento/patología , Homeostasis/efectos de los fármacos , Iones , Riñón/efectos de los fármacos , Riñón/metabolismo , Ratones Endogámicos C57BL , Minerales/metabolismo , Compuestos de Fenilurea/uso terapéutico , Pirimidinas/uso terapéutico , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Raquitismo Hipofosfatémico/tratamiento farmacológico , Raquitismo Hipofosfatémico/patología , Cola (estructura animal)/anatomía & histología , Vitamina D/análogos & derivados , Vitamina D/biosíntesis
12.
Int J Gynecol Cancer ; 22(9): 1517-26, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23060048

RESUMEN

OBJECTIVE: The fibroblast growth factor (FGF) family of signaling molecules has been associated with chemoresistance and poor prognosis in a number of cancer types, including lung, breast, ovarian, prostate, and head and neck carcinomas. Given the identification of activating mutations in the FGF receptor 2 (FGFR2) receptor tyrosine kinase in a subset of endometrial tumors, agents with activity against FGFRs are currently being tested in clinical trials for recurrent and progressive endometrial cancer. Here, we evaluated the effect of FGFR inhibition on the in vitro efficacy of chemotherapy in endometrial cancer cell lines. METHODS: Human endometrial cancer cell lines with wild-type or activating FGFR2 mutations were used to determine any synergism with concurrent use of the pan-FGFR inhibitor, PD173074, and the chemotherapeutics, doxorubicin and paclitaxel, on cell proliferation and apoptosis. RESULTS: FGFR2 mutation status did not alter sensitivity to either chemotherapeutic agent alone. The combination of PD173074 with paclitaxel or doxorubicin showed synergistic activity in the 3 FGFR2 mutant cell lines evaluated. In addition, although nonmutant cell lines were resistant to FGFR inhibition alone, the addition of PD173074 potentiated the cytostatic effect of paclitaxel and doxorubicin in a subset of FGFR2 wild-type endometrial cancer cell lines. CONCLUSIONS: Together these data suggest a potential therapeutic benefit to combining an FGFR inhibitor with standard chemotherapeutic agents in endometrial cancer therapy particularly in patients with FGFR2 mutation positive tumors.


Asunto(s)
Carcinoma Endometrioide/patología , Doxorrubicina/farmacología , Neoplasias Endometriales/patología , Paclitaxel/farmacología , Pirimidinas/farmacología , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Carcinoma Endometrioide/tratamiento farmacológico , Carcinoma Endometrioide/genética , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Evaluación Preclínica de Medicamentos , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Sinergismo Farmacológico , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/genética , Femenino , Humanos , Mutación/fisiología , Paclitaxel/administración & dosificación , Pirimidinas/administración & dosificación , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismo , Receptores de Factores de Crecimiento de Fibroblastos/genética , Células Tumorales Cultivadas
13.
Magy Onkol ; 56(3): 199-208, 2012 Sep.
Artículo en Húngaro | MEDLINE | ID: mdl-23008829

RESUMEN

Angiogenesis is essential for tumor growth and metastasis. The main regulators of the process are the signaling cascades of VEGF-, PDGF- and FGF receptors. Inhibition of these pathways holds potential therapeutic benefit not only for cancer patients, but also for the treatment of other diseases. This paper summarizes the experimental and clinical results of studies available so far on the multi-target tyrosine kinase inhibitor nintedanib (BIBF 1120). According to these studies, nintedanib effectively inhibits VEGFR-, PDGFR- and FGFR signalization and thus the proliferation and survival of cell types which highly express these receptors (i.e. endothelial and smooth muscle cells and pericytes). In vitro studies and in vivo xenograft experiments have provided promising results. In the clinical setting, BIBF 1120 seems to be effective and well tolerated in various tumor types, such as lung, prostate, colorectal and hepatocellular carcinoma, as well as in gynecological tumors. The main adverse events are gastrointestinal toxicities and the reversible elevation of liver enzyme levels. Nintedanib might also be combined with paclitaxel, carboplatin, pemetrexed and docetaxel. There are several ongoing clinical trials testing the efficacy of BIBF 1120.


Asunto(s)
Antineoplásicos/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Indoles/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Axitinib , Bencenosulfonatos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Ensayos Clínicos como Asunto , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Sistema Digestivo/efectos de los fármacos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacología , Femenino , Neoplasias de los Genitales Femeninos/tratamiento farmacológico , Neoplasias de los Genitales Femeninos/metabolismo , Humanos , Imidazoles/uso terapéutico , Indazoles/uso terapéutico , Indoles/administración & dosificación , Indoles/efectos adversos , Indoles/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Neoplasias/enzimología , Neoplasias/patología , Niacinamida/análogos & derivados , Niacinamida/uso terapéutico , Oligonucleótidos , Compuestos de Fenilurea , Ftalazinas/uso terapéutico , Piperidinas/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Piridinas/uso terapéutico , Pirimidinas/uso terapéutico , Quinazolinas/uso terapéutico , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Transducción de Señal/efectos de los fármacos , Sorafenib
14.
Phytother Res ; 26(1): 122-6, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21567511

RESUMEN

Curcumin (diferuloylmethane) is a phenolic compound present in turmeric and is ingested daily in many parts of the world. Curcumin has been reported to cause inhibition on proliferation and induction of apoptosis in many human cancer cell lines, including non-small cell lung cancer cells (NSCLC). However, the clinical application of curcumin is restricted by its low bioavailability. In this report, it was observed that combined treatment of a low dosage of curcumin (5-10 µM) with a low concentration (0.1-2.5 µM) of small molecule inhibitors, including AG1478, AG1024, PD173074, LY294002 and caffeic acid phenethyl ester (CAPE) increased the growth inhibition in two human NSCLC cell lines: A549 and H1299 cells. The observation suggested that combined treatment of a low dosage of curcumin with inhibitors against epidermal growth factor receptor (EGFR), insulin-like growth factor 1 (IGF-1R), fibroblast growth factors receptor (FGFR), phosphatidylinositol 3-kinases (PI3K) or NF-κB signaling pathway may be a potential adjuvant therapy beneficial to NSCLC patients.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Curcuma/química , Curcumina/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Fitoterapia , Extractos Vegetales/uso terapéutico , Antineoplásicos/farmacología , Disponibilidad Biológica , Ácidos Cafeicos/farmacología , Ácidos Cafeicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cromonas/farmacología , Cromonas/uso terapéutico , Curcumina/farmacología , Quimioterapia Combinada , Inhibidores Enzimáticos/farmacología , Receptores ErbB/antagonistas & inhibidores , Humanos , Morfolinas/farmacología , Morfolinas/uso terapéutico , FN-kappa B/antagonistas & inhibidores , Alcohol Feniletílico/análogos & derivados , Alcohol Feniletílico/farmacología , Alcohol Feniletílico/uso terapéutico , Inhibidores de las Quinasa Fosfoinosítidos-3 , Extractos Vegetales/farmacología , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Quinazolinas/farmacología , Quinazolinas/uso terapéutico , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Somatomedinas/antagonistas & inhibidores , Tirfostinos/farmacología , Tirfostinos/uso terapéutico
15.
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
16.
Cancer Res ; 71(4): 1396-405, 2011 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-21212416

RESUMEN

Tumor angiogenesis is a degenerate process regulated by a complex network of proangiogenic factors. Existing antiangiogenic drugs used in clinic are characterized by selectivity for specific factors. Antiangiogenic properties might be improved in drugs that target multiple factors and thereby address the inherent mechanistic degeneracy in angiogenesis. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) family members and their cognate receptors are key players in promoting tumor angiogenesis. Here we report the pharmacologic profile of E-3810, a novel dual inhibitor of the VEGF and FGF receptors. E-3810 potently and selectively inhibited VEGF receptor (VEGFR)-1, -2, and -3 and FGF receptor (FGFR)-1 and -2 kinases in the nanomolar range. Ligand-dependent phosphorylation of VEGFR-2 and FGFR-1 was suppressed along with human vascular endothelial cell growth at nanomolar concentrations. In contrast, E-3810 lacked cytotoxic effects on cancer cell lines under millimolar concentrations. In a variety of tumor xenograft models, including early- or late-stage subcutaneous and orthotopic models, E-3810 exhibited striking antitumor properties at well-tolerated oral doses administered daily. We found that E-3810 remained active in tumors rendered nonresponsive to the general kinase inhibitor sunitinib resulting from a previous cycle of sunitinib treatment. In Matrigel plug assays performed in nude mice, E-3810 inhibited basic FGF-induced angiogenesis and reduced blood vessel density as assessed by histologic analysis. Dynamic contrast-enhanced magnetic resonance imaging analysis confirmed that E-3810 reduced the distribution of angiogenesis-sensitive contrast agents after only 5 days of treatment. Taken together, our findings identify E-3810 as a potent antiangiogenic small molecule with a favorable pharmacokinetic profile and broad spectrum antitumor activity, providing a strong rationale for its clinical evaluation.


Asunto(s)
2-Piridinilmetilsulfinilbencimidazoles/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , 2-Piridinilmetilsulfinilbencimidazoles/farmacología , Animales , Antineoplásicos/farmacología , Células Cultivadas , Evaluación Preclínica de Medicamentos , Femenino , Células HT29 , Células Hep G2 , Humanos , Ratones , Ratones Desnudos , Modelos Biológicos , Células 3T3 NIH , Neoplasias/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Rabeprazol , Ensayos Antitumor por Modelo de Xenoinjerto
17.
Mol Pharm ; 7(5): 1545-60, 2010 Oct 04.
Artículo en Inglés | MEDLINE | ID: mdl-20712327

RESUMEN

Multitarget agents have been increasingly explored for enhancing efficacy and reducing countertarget activities and toxicities. Efficient virtual screening (VS) tools for searching selective multitarget agents are desired. Combinatorial support vector machines (C-SVM) were tested as VS tools for searching dual-inhibitors of 11 combinations of 9 anticancer kinase targets (EGFR, VEGFR, PDGFR, Src, FGFR, Lck, CDK1, CDK2, GSK3). C-SVM trained on 233-1,316 non-dual-inhibitors correctly identified 26.8%-57.3% (majority >36%) of the 56-230 intra-kinase-group dual-inhibitors (equivalent to the 50-70% yields of two independent individual target VS tools), and 12.2% of the 41 inter-kinase-group dual-inhibitors. C-SVM were fairly selective in misidentifying as dual-inhibitors 3.7%-48.1% (majority <20%) of the 233-1,316 non-dual-inhibitors of the same kinase pairs and 0.98%-4.77% of the 3,971-5,180 inhibitors of other kinases. C-SVM produced low false-hit rates in misidentifying as dual-inhibitors 1,746-4,817 (0.013%-0.036%) of the 13.56 M PubChem compounds, 12-175 (0.007%-0.104%) of the 168 K MDDR compounds, and 0-84 (0.0%-2.9%) of the 19,495-38,483 MDDR compounds similar to the known dual-inhibitors. C-SVM was compared to other VS methods Surflex-Dock, DOCK Blaster, kNN and PNN against the same sets of kinase inhibitors and the full set or subset of the 1.02 M Zinc clean-leads data set. C-SVM produced comparable dual-inhibitor yields, slightly better false-hit rates for kinase inhibitors, and significantly lower false-hit rates for the Zinc clean-leads data set. Combinatorial SVM showed promising potential for searching selective multitarget agents against intra-kinase-group kinases without explicit knowledge of multitarget agents.


Asunto(s)
Evaluación Preclínica de Medicamentos/métodos , Inhibidores de Proteínas Quinasas/farmacología , Máquina de Vectores de Soporte , Interfaz Usuario-Computador , Antineoplásicos/química , Antineoplásicos/farmacología , Proteína Quinasa CDC2/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Diseño de Fármacos , Receptores ErbB/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Humanos , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Familia-src Quinasas/antagonistas & inhibidores
18.
J Exp Clin Cancer Res ; 28: 151, 2009 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-20003343

RESUMEN

BACKGROUND: Many experimental data evidence that over-expression of various growth factors cause disorders in cell proliferation. The role of the Fibroblast Growth Factors (FGF) in growth control is indisputable: in particular, FGF1 and its tyrosine kinase receptor (FGFR1) act through a very complex network of mechanisms and pathways. In this work we have evaluated the antiproliferative activity effect of PD166866, a synthetic molecule inhibiting the tyrosin kinase action of FGFR1. METHODS: Cells were routinely grown in Dulbecco Modified Eagle's medium supplemented with newborn serum and a penicillin-streptomycin mixture.Cell viability was evaluated by Mosmann assay and by trypan blue staining. DNA damage was assessed by in situ fluorescent staining with Terminal Deoxynucleotidyl Transferase dUTP nick end labeling (TUNEL assay).Assessment of oxidative stress at membrane level was measured by quantitative analysis of the intra-cellular formation of malonyl-dialdheyde (MDA) deriving from the decomposition of poly-unsaturated fatty acids.The expression of Poly-ADP-Ribose-Polymerase (PARP), consequent to DNA fragmentation, was evidenced by immuno-histochemistry utilizing an antibody directed against an N-terminal fragment of the enzyme. RESULTS: The bioactivity of the drug was investigated on Hela cells. Cytoxicity was assessed by the Mosmann assay and by vital staining with trypan blue. The target of the molecule is most likely the cell membrane as shown by the significant increase of the intracellular concentration of malonyl-dihaldheyde. The increase of this compound, as a consequence of the treatment with PD166866, is suggestive of membrane lipoperoxidation. The TUNEL assay gave a qualitative, though clear, indication of DNA damage. Furthermore we demonstrate intracellular accumulation of poly-ADP-ribose polymerase I. This enzyme is a sensor of nicks on the DNA strands and this supports the idea that treatment with the drug induces cell death. CONCLUSIONS: Data presented in this work show that PD166866 has clear antiproliferative effects. The negative control of cell proliferation may be exerted through the activation of the apoptotic pathway. The results of experiments addressing this specific point, such as: evaluation of DNA damage, lipoperoxidation of the cell membrane and increase of expression of PARP, an enzyme directly involved in DNA repair. Results suggest that cells exposed to PD16866 undergo apoptosis. However, concomitant modes of cell death cannot be ruled out. The possible use of this drug for therapeutic purposes is discussed.


Asunto(s)
Pirimidinas/farmacología , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Urea/análogos & derivados , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Daño del ADN , Células HeLa , Humanos , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Urea/farmacología
19.
Comb Chem High Throughput Screen ; 9(2): 95-102, 2006 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-16475967

RESUMEN

The process of Drug Discovery is a complex and high risk endeavor that requires focused attention on experimental hypotheses, the application of diverse sets of technologies and data to facilitate high quality decision-making. All is aimed at enhancing the quality of the chemical development candidate(s) through clinical evaluation and into the market. In support of the lead generation and optimization phases of this endeavor, high throughput technologies such as combinatorial/high throughput synthesis and high throughput and ultra-high throughput screening, have allowed the rapid analysis and generation of large number of compounds and data. Today, for every analog synthesized 100 or more data points can be collected and captured in various centralized databases. The analysis of thousands of compounds can very quickly become a daunting task. In this article we present the process we have developed for both analyzing and prioritizing large sets of data starting from diversity and focused uHTS in support of lead generation and secondary screens supporting lead optimization. We will describe how we use informatics and computational chemistry to focus our efforts on asking relevant questions about the desired attributes of a specific library, and subsequently in guiding the generation of more information-rich sets of analogs in support of both processes.


Asunto(s)
Química Farmacéutica/métodos , Técnicas Químicas Combinatorias/métodos , Biología Computacional/métodos , Programas Informáticos , Bases de Datos Factuales , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores
20.
Dev Biol ; 274(1): 139-57, 2004 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-15355794

RESUMEN

We have investigated fibroblast growth factor (FGF) signaling during the development of the zebrafish pharyngeal dentition with the goal of uncovering novel roles for FGFs in tooth development as well as phylogenetic and topographic diversity in the tooth developmental pathway. We found that the tooth-related expression of several zebrafish genes is similar to that of their mouse orthologs, including both epithelial and mesenchymal markers. Additionally, significant differences in gene expression between zebrafish and mouse teeth are indicated by the apparent lack of fgf8 and pax9 expression in zebrafish tooth germs. FGF receptor inhibition with SU5402 at 32 h blocked dental epithelial morphogenesis and tooth mineralization. While the pharyngeal epithelium remained intact as judged by normal pitx2 expression, not only was the mesenchymal expression of lhx6 and lhx7 eliminated as expected from mouse studies, but the epithelial expression of dlx2a, dlx2b, fgf3, and fgf4 was as well. This latter result provides novel evidence that the dental epithelium is a target of FGF signaling. However, the failure of SU5402 to block localized expression of pitx2 suggests that the earliest steps of tooth initiation are FGF-independent. Investigations of specific FGF ligands with morpholino antisense oligonucleotides revealed only a mild tooth shape phenotype following fgf4 knockdown, while fgf8 inhibition revealed only a subtle down-regulation of dental dlx2b expression with no apparent effect on tooth morphology. Our results suggest redundant FGF signals target the dental epithelium and together are required for dental morphogenesis. Further work will be required to elucidate the nature of these signals, particularly with respect to their origins and whether they act through the mesenchyme.


Asunto(s)
Factores de Crecimiento de Fibroblastos/metabolismo , Regulación del Desarrollo de la Expresión Génica/fisiología , Transducción de Señal/fisiología , Diente/embriología , Pez Cebra/embriología , Animales , Secuencia de Bases , Análisis por Conglomerados , ADN Complementario/genética , Epitelio/metabolismo , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Técnicas Histológicas , Proteínas de Homeodominio/genética , Hibridación in Situ , Proteínas con Homeodominio LIM , Ligandos , Datos de Secuencia Molecular , Morfogénesis , Proteínas del Tejido Nervioso/genética , Oligonucleótidos Antisentido , Pirroles/farmacología , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ADN , Factores de Transcripción
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