RESUMEN
Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy is the primary treatment option for patients with non-small cell lung cancer (NSCLC). However, one of the major adverse effects associated with this therapy is skin toxicity, which impacts the patient's quality of life. This study aimed to describe the severities and locations of skin toxicity, and to analyze their association with the quality of life in patients with advanced NSCLC who received EGFR-TKI therapy as first-line treatment.This cross-sectional and correlation study was conducted at a tertiary medical center in northern Taiwan between July 2015 and March 2016. Skin toxicity was assessed and graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). The Skindex-16 scale was used to measure the skin disease-related quality of life.A total of 146 NSCLC patients who received EGFR-TKI therapy within the first 3 months of diagnosis were included in this study; 93.2% of these patients experienced skin toxicities. Approximately 70% of the patients developed xerosis and pruritus, while 50% had papulopustular eruptions and paronychia. The mean skin symptom impact score was 5.38 (standard deviationâ=â2.65). The skin-related quality of life varied widely among the participants but remained acceptable (mean scoreâ=â13.96, standard deviationâ=â16.55). Skin symptoms correlated significantly with poor quality of life (râ=â0.50, Pâ<â.001). Younger patients and those treated with afatinib were the most affected, reporting the poorest quality of life. Patients who required EGFR-TKI dose reduction had experienced more severe skin symptoms than had patients who did not require it (7.35 vs 5.01, Pâ<â.001).Skin toxicity related to EGFR-TKI treatment impacts the quality of life in patients with NSCLC. During the treatment period, skin assessment and tailored management should be incorporated into the daily care plan.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/normas , Piel/efectos de los fármacos , Afatinib/efectos adversos , Afatinib/normas , Afatinib/uso terapéutico , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/psicología , Correlación de Datos , Estudios Transversales , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/fisiopatología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/psicología , Clorhidrato de Erlotinib/efectos adversos , Clorhidrato de Erlotinib/normas , Clorhidrato de Erlotinib/uso terapéutico , Femenino , Gefitinib/efectos adversos , Gefitinib/normas , Gefitinib/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/uso terapéutico , Calidad de Vida/psicología , Piel/fisiopatología , Encuestas y Cuestionarios , Taiwán/epidemiologíaRESUMEN
The EphA2 receptor has been validated in animal models as new target for treating tumors depending on angiogenesis and vasculogenic mimicry. In the present work, we extended our current knowledge on structure-activity relationship (SAR) data of two related classes of antagonists of the EphA2 receptor, namely 5ß-cholan-24-oic acids and 5ß-cholan-24-oyl l-ß-homotryptophan conjugates, with the aim to develop new antiangiogenic compounds able to efficiently prevent the formation of blood vessels. As a result of our exploration, we identified UniPR505, N-[3α-(Ethylcarbamoyl)oxy-5ß-cholan-24-oyl]-l-ß-homo-tryptophan (compound 14), as a submicromolar antagonist of the EphA2 receptor capable to block EphA2 phosphorylation and to inhibit neovascularization in a chorioallantoic membrane (CAM) assay.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/normas , Ácido Litocólico/química , Neovascularización Fisiológica/efectos de los fármacos , Compuestos Policíclicos/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Receptor EphA2/antagonistas & inhibidores , Inhibidores de la Angiogénesis/química , Animales , Proliferación Celular , Embrión de Pollo , Pollos , Membrana Corioalantoides , Humanos , Masculino , Modelos Moleculares , Fosforilación , Compuestos Policíclicos/química , Neoplasias de la Próstata/patología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/normas , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
INTRODUCTION: Oral tyrosine kinase inhibitors targeting the chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) in non-small cell lung cancer (NSCLC) were associated with superior clinical outcome. Tyrosine Kinase inhibitors (TKIs) are known to have peculiar toxicity profile, hence, increasing awareness to the safety profile of ALK inhibitors is essential. METHODS: A comprehensive systematic review of literature has been conducted to include prospective trials that used the ALK inhibitors Crizotinib, Ceritinib, Alectinib, Brigatinib and Lorlatinib in patients with advanced NSCLC and have available efficacy and toxicity results. RESULTS: A total of 14 studies including 2793 patients were considered eligible for our review and included two phase IB, seven phase II and five phase III studies. The most common adverse events (AEs) observed with ALK inhibitors were gastrointestinal (GI) toxicities as nausea (up to 83%), vomiting (up to 67%) and diarrhea (up to 86%), elevation of liver enzymes occurred in up to 60% and fatigue (up to 43%). There were differences in the toxicity patterns between the different ALK inhibitors with more GI and hepatic toxicities with Ceritinib, more visual disorders with Crizotinib, more dysgeusia with crizotinib and Alectinib and possibly more respiratory complications with Brigatinib. Most of the AEs were low grade and treatment-related deaths were associated with ALK inhibitors in 0-1% of patients. CONCLUSION: Most of adverse effects of ALKi can be managed efficiently via dose modifications or interruptions. Timely identification of each ALKi pattern of toxicity can prevent treatment-related morbidity and mortality in this palliative setting.
Asunto(s)
Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/normas , Inhibidores de Proteínas Quinasas/uso terapéutico , Humanos , SeguridadRESUMEN
The NCCN Guidelines for Thyroid Carcinoma provide recommendations for the management of different types of thyroid carcinoma, including papillary, follicular, Hürthle cell, medullary, and anaplastic carcinomas. These NCCN Guidelines Insights summarize the panel discussion behind recent updates to the guidelines, including the expanding role of molecular testing for differentiated thyroid carcinoma, implications of the new pathologic diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features, and the addition of a new targeted therapy option for BRAF V600E-mutated anaplastic thyroid carcinoma.
Asunto(s)
Carcinoma/terapia , Oncología Médica/normas , Neoplasias de la Tiroides/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/normas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma/diagnóstico , Carcinoma/mortalidad , Carcinoma/patología , Ensayos Clínicos como Asunto , Humanos , Biopsia Guiada por Imagen/métodos , Biopsia Guiada por Imagen/normas , Estadificación de Neoplasias , Pronóstico , Inhibidores de Proteínas Quinasas/normas , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Sociedades Médicas/normas , Glándula Tiroides/diagnóstico por imagen , Glándula Tiroides/patología , Glándula Tiroides/cirugía , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Tiroidectomía/métodos , Tiroidectomía/normas , Resultado del Tratamiento , Estados UnidosRESUMEN
Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph), resulting from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor (TKI) therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML (CP-CML). The selection TKI therapy should be based on the risk score, toxicity profile of TKI, patient's age, ability to tolerate therapy, and the presence of comorbid conditions. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CP-CML.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Oncología Médica/normas , Inhibidores de Proteínas Quinasas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/normas , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/aislamiento & purificación , Médula Ósea/patología , Ensayos Clínicos como Asunto , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos/genética , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/aislamiento & purificación , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Oncología Médica/métodos , Selección de Paciente , Cromosoma Filadelfia , Pronóstico , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/normas , Reacción en Cadena en Tiempo Real de la Polimerasa/normas , Medición de Riesgo/métodos , Medición de Riesgo/normas , Sociedades Médicas/normas , Estados UnidosRESUMEN
BACKGROUND: Mutations in the FMS-like tyrosine kinase 3 (FLT3) are associated with uncontrolled cellular functions that contribute to the development of acute myeloid leukaemia (AML). We performed computer simulations of the FLT3-dependent signalling network in order to study the pathways that are involved in AML development and resistance to targeted therapies. RESULTS: Analysis of the simulations revealed the presence of alternative pathways through phosphoinositide 3 kinase (PI3K) and SH2-containing sequence proteins (SHC), that could overcome inhibition of FLT3. Inhibition of cyclin dependent kinase 6 (CDK6), a related molecular target, was also tested in the simulation but was not found to yield sufficient benefits alone. CONCLUSIONS: The PI3K pathway provided a basis for resistance to treatments. Alternative signalling pathways could not, however, restore cancer growth signals (proliferation and loss of apoptosis) to the same levels as prior to treatment, which may explain why FLT3 resistance mutations are the most common resistance mechanism. Finally, sensitivity analysis suggested the existence of optimal doses of FLT3 and CDK6 inhibitors in terms of efficacy and toxicity.
Asunto(s)
Simulación por Computador , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Leucemia Mieloide Aguda/patología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/normas , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Quinasa 6 Dependiente de la Ciclina/genética , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Mutación , Transducción de Señal/efectos de los fármacos , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
A sensitive, specific, selective and rapid LC-ESI-MS/MS method has been developed and validated for the quantification of defactinib in mice plasma using 13C3,15N-tofacitinib as an internal standard (I.S.). Sample preparation was accomplished through a liquid-liquid extraction process. Baseline chromatographic resolution of defactinib and the I.S. was achieved on an Atlantis dC18 column using an isocratic mobile phase comprising 0.2% formic acid in water and acetonitrile (25:75, v/v) delivered at a flow rate of 0.5mL/min. Defactinib and the I.S. eluted at â¼1.59 and 0.99min, respectively. The total chromatographic run time was 2.50min. A linear response function was established in the concentration range of 0.13-106 ng/mL. Method validation was performed as per regulatory guidelines and the results met the acceptance criteria. The intra- and inter-day accuracy and precision were in the range of 5.57-13.3 and 8.63-12.1%, respectively. Defactinib was found to be stable under various stability conditions. This novel method has been applied to a pharmacokinetic study in mice.
Asunto(s)
Benzamidas/farmacocinética , Quinasa 1 de Adhesión Focal/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacocinética , Pirazinas/farmacocinética , Espectrometría de Masa por Ionización de Electrospray/métodos , Sulfonamidas/farmacocinética , Espectrometría de Masas en Tándem/métodos , Animales , Área Bajo la Curva , Benzamidas/sangre , Benzamidas/toxicidad , Isótopos de Carbono/química , Cromatografía Líquida de Alta Presión/instrumentación , Cromatografía Líquida de Alta Presión/métodos , Estabilidad de Medicamentos , Límite de Detección , Extracción Líquido-Líquido , Masculino , Ratones , Ratones Endogámicos BALB C , Isótopos de Nitrógeno/química , Piperidinas/química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/normas , Inhibidores de Proteínas Quinasas/toxicidad , Pirazinas/sangre , Pirazinas/toxicidad , Pirimidinas/química , Pirroles/química , Estándares de Referencia , Reproducibilidad de los Resultados , Sulfonamidas/sangre , Sulfonamidas/toxicidadRESUMEN
MELK kinase has been implicated in playing an important role in tumorigenesis. Our previous studies suggested that MELK is involved in the regulation of cell cycle and its genetic depletion leads to growth inhibition in a subset of high MELK-expressing basal-like breast cancer cell lines. Herein we describe the discovery and optimization of novel MELK inhibitors 8a and 8b that recapitulate the cellular effects observed by short hairpin ribonucleic acid (shRNA)-mediated MELK knockdown in cellular models. We also discovered a novel fluorine-induced hydrophobic collapse that locked the ligand in its bioactive conformation and led to a 20-fold gain in potency. These novel pharmacological inhibitors achieved high exposure in vivo and were well tolerated, which may allow further in vivo evaluation.
Asunto(s)
Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/normas , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Células MCF-7 , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Relación Estructura-ActividadRESUMEN
Diabetic neuropathy is a common complication of diabetes mellitus affecting 30-50% of patients and is a major cause for increased costs, morbidity and mortality. Strict diabetes control prevents this complication and may restore neurologic deficits in the early stages. Several efforts have been undertaken to alter the natural history of this complication, including the use of aldose reductase and protein kinase-C inhibitors, as well as antioxidants. Available data so far do not support the use of aldose reductase inhibitors due to safety issues and efficacy. Protein kinase-C inhibitors have provided encouraging initial results but their development has been halted. Antioxidants, like a-lipoic acid, improve some neurological deficits and painful symptoms. There are effective and safe medications such as anticonvulsants, antidepressants and opioids for the management of patients with painful symptoms. In this revew we present standard and emerging treatment modalities for the etiologic and symptomatic treatment of diabetic neuropathy.
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Analgésicos Opioides/uso terapéutico , Anticonvulsivantes/uso terapéutico , Antidepresivos/uso terapéutico , Antioxidantes/uso terapéutico , Neuropatías Diabéticas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Analgésicos Opioides/normas , Anticonvulsivantes/normas , Antidepresivos/normas , Antioxidantes/normas , Neuropatías Diabéticas/complicaciones , Neuropatías Diabéticas/metabolismo , Humanos , Inhibidores de Proteínas Quinasas/normasRESUMEN
Imatimib mesylate is a drug for the treatment of gastrointestinal stroma tumor and chronic myelogenous leukemia. In this study, capillary electrophoretic analysis of imatinib mesylate and related compounds was developed. The optimized separation condition was NaH(2)PO(4) (10 mM) aqueous solution containing 5 mM of 2-hydroxypropyl-ß-cyclodextrin at a pH of 2.0. The separation could be obtained in less than 20 min when the separation voltage was 20 kV. To enhance the sensitivity, field amplified sample stacking combining with large volume sample injection was adopted. The optimal injection conditions were obtained by using methanol containing 0.5 mM HCl as the sample dilution solution and performing injection at a voltage of 15 kV for 60 s. The linearity ranges of ima amine, N-desmethyl imatinib and imatinib mesylate were 0.005-0.500 µg/ml, and 4-chloromethyl-N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide was 0.010-0.500 µg/ml, with good linear correlation coefficients (r(2)>0.9900). The intra-day and inter-day relative standard deviations of peak areas were satisfactory. Under the optimized condition, five batches of the synthesized samples were detected and ima amine was found in all the batches. Due to its simplicity, effectiveness and low price, the developed method can be used for quality control analysis of imatinib mesylate.
Asunto(s)
Antineoplásicos/análisis , Electroforesis Capilar/métodos , Piperazinas/análisis , Inhibidores de Proteínas Quinasas/análisis , Pirimidinas/análisis , 2-Hidroxipropil-beta-Ciclodextrina , Antineoplásicos/normas , Benzamidas , Tampones (Química) , Contaminación de Medicamentos , Concentración de Iones de Hidrógeno , Hidrólisis , Mesilato de Imatinib , Fosfatos/química , Piperazinas/normas , Inhibidores de Proteínas Quinasas/normas , Pirimidinas/normas , Control de Calidad , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Solventes/química , beta-Ciclodextrinas/químicaRESUMEN
Viral replication and pathogenesis involves many cellular protein kinases, and many specific inhibitors of such kinase have been developed for the treatment of noninfectious diseases. As expected, such drugs have been repeatedly demonstrated to inhibit viral replication in cultured cells. Cellular protein kinases have thus been considered for several years as potentially valid targets for antiviral therapy. However, until recently there was no proof of such activity in vivo. The three papers discussed herein demonstrate that inhibitors of cellular protein kinases are indeed effective for the treatment of virus-induced disease in animal models and human clinical trials.
Asunto(s)
Antivirales/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Animales , Antivirales/normas , Benzamidas , Herpesvirus Humano 8/efectos de los fármacos , Humanos , Mesilato de Imatinib , Ratones , Piperazinas/normas , Piperazinas/uso terapéutico , Poxviridae/efectos de los fármacos , Inhibidores de Proteínas Quinasas/normas , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/normas , Pirimidinas/uso terapéutico , Replicación Viral/efectos de los fármacosRESUMEN
Protein kinases play key roles in a number of diseases, including cancer, inflammation, and diabetes. Disregulation of kinase-based signal transduction networks results in aberrant cell differentiation, activation, proliferation, and invasion. The growing importance of kinases as a major class of drug targets across multiple large clinical indications, together with the large number of kinases in the genome (~518), has generated a critical need for technologies that enable the identification of potent and selective kinase inhibitors with good drug-like properties. In this review, we describe methods used for developing cell-based assays for kinase inhibitors, discuss advantages and disadvantages of each approach, and describe new chemical genetic methods as reference systems for establishing cell-based assays and their use for functional selectivity profiling of kinase inhibitors.