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1.
Endocrinol. diabetes nutr. (Ed. impr.) ; 66(8): 472-479, oct. 2019. ^f472^l479
Artigo em Espanhol | IBECS | ID: ibc-184140

RESUMO

Antecedentes y objetivo: El tratamiento con antineoplásicos orales tipo inhibidores de tirosina quinasa (ITK) es novedoso, y por ello se conoce poco sobre cómo afectan al estado nutricional (EN), la ingesta dietética, la calidad de vida, y su influencia sobre la supervivencia. Este estudio pretende aportar información sobre estos componentes, para dirigir las recomendaciones nutricionales futuras. Pacientes y método: Estudio prospectivo y observacional en adultos que inician ITK, donde se valoró el EN mediante el cuestionario de valoración subjetiva global generada por el paciente (VSG-GP), medidas antropométricas, parámetros bioquímicos e ingesta dietética (Recuerdo de 24 h). La calidad de vida se estudió con EORTC QLQ-C30. El análisis estadístico empleó pruebas no paramétricas y la supervivencia se analizó mediante curvas de Kaplan-Meier y log-rank. Resultados: El 21,7% de la muestra presentó desnutrición moderada según VSG-GP; el 74,2% mostró pérdida de peso moderada a los 6 meses, aunque ningún paciente tuvo un IMC < 18,5 kg/m2. Los pacientes moderadamente desnutridos presentaron menor supervivencia a los 4 años del diagnóstico (log-rank = 0,015). El 44,4% realizó una ingesta energética inferior a las recomendaciones ESPEN 2017 y ningún paciente cubrió requerimientos proteicos (1,5 g proteína/kg peso) durante el seguimiento. Una peor puntuación en la escala global de salud del EORTC QLQ-C30 se relacionó con peor EN. Conclusiones: El tratamiento con ITK no parece afectar de manera importante el EN y la calidad de vida a los 6 meses de seguimiento. Se debe prevenir la desnutrición, mediante un consejo nutricional individualizado, pues se relaciona con menor supervivencia


Background and objective: Treatment with oral antineoplastic agents known as tyrosine kinase inhibitors (TKIs) is new and, thus, little is known about their impact on nutritional status (NS), dietary intake, quality of life, and survival. The aim of this study was to provide information on these components in order to guide future nutritional recommendations. Patients and method: A prospective, observational study in adults who start treatment with TKIs, in whom NS was assessed using the Patient-Generated Subjective Global Assessment (PG-SGA), anthropometric measures, biochemical parameters, and dietary intake (24-hour dietary recall). The EORTC QLQ-C30 was used to assess quality of life. Nonparametric tests were used in statistical analysis, and survival was analyzed using Kaplan-Meier and log-rank curves. Results: Of the overall sample, 21.7% had moderate malnutrition according to PG-SGA, and 74.2% moderate weight loss at 6 months, but no patient had BMI < 18.5 kg/m2. Patients with moderate malnutrition had lower survival at four years of diagnosis (log-rank = 0.015). Energy intake was lower than recommended by the ESPEN 2017 congress, and no patient covered the protein requirements (1.5 g protein/kg weight) during follow-up. A worse score on the global health scale of the EORTC QLQ-C30 was related to worse NS. Conclusions: Treatment with TKIs does not appear to have a significant impact on NS and quality of life after 6 months of follow-up. Malnutrition should be prevented through individualized nutritional advice because it is related to shorter survival


Assuntos
Humanos , Adulto , Sobrevivência , Neoplasias/epidemiologia , Estado Nutricional , Proteínas Tirosina Quinases/antagonistas & inibidores , Qualidade de Vida , Neoplasias/dietoterapia , Estudos Prospectivos , Inquéritos e Questionários , Antropometria , Dietoterapia , Dietética
2.
Medicine (Baltimore) ; 98(42): e17588, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626129

RESUMO

In 2014/2015, tyrosine kinase inhibitors (TKIs) were introduced as a secondary treatment for refractory differentiated thyroid cancer (DTC) in Japan. While renal dysfunction is an adverse event of TKI, data on this adverse event in TKI-treated DTC remains insufficient. Here, we investigated renal function in patients undergoing TKI treatment for DTC and evaluated the efficacy of dose reduction/withdrawal for cases of renal dysfunction.A total of 73 cases of radioactive iodine-refractory DTC treated with sorafenib (n = 22) or lenvatinib (n = 51) were included. Patient data evaluated were TKI treatment period, estimated glomerular filtration rate (eGFR) before and after TKI therapy, incidence and degree (maximum value at time of TKI treatment) of proteinuria, and albumin levels before and after TKI therapy were compared.The mean ΔeGFR was -6.75% with lenvatinib and +5.90% with sorafenib. It was not significant (P = .15). The mean Δalbumin was -8.90% and -5.85% with lenvatinib and sorafenib, respectively; there was no significant difference between the lenvatinib and sorafenib groups (P = .77). According to our program of TKI dose reduction and withdrawal, all patients except 2 with diabetes were successfully continuing treatment.Overall, the present results demonstrated that renal function is negatively affected by long-term TKI treatment for RAI-refractory DTC. However, heightened proteinuria, decreased eGFR and albumin levels, and significant but apparently reversible renal dysfunction were more frequent with lenvatinib than sorafenib.


Assuntos
Taxa de Filtração Glomerular/fisiologia , Radioisótopos do Iodo/uso terapêutico , Nefropatias/etiologia , Compostos de Fenilureia/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinolinas/uso terapêutico , Sorafenibe/uso terapêutico , Neoplasias da Glândula Tireoide/terapia , Idoso , Substituição de Medicamentos , Feminino , Seguimentos , Humanos , Nefropatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Tolerância a Radiação , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/complicações , Neoplasias da Glândula Tireoide/diagnóstico , Tomografia Computadorizada por Raios X , Resultado do Tratamento
3.
Drugs ; 79(12): 1277-1286, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31313100

RESUMO

ROS1 gene rearrangements exist in 1-2% of non-small cell lung cancers, typically occurring in younger, never or light smokers with adenocarcinoma. ROS1 gene fusions are potent oncogenic drivers, the presence of which results in the susceptibility of tumours to ROS1-targeted therapy. Crizotinib was the first tyrosine kinase inhibitor to demonstrate activity in ROS1-rearranged lung cancer, and remains the recommended first-line therapy for patients with advanced ROS1-rearranged non-small cell lung cancer. Despite excellent initial responses to crizotinib, the majority of patients develop disease progression, which may be intracranial or extracranial. Identification of resistance mechanisms to crizotinib, and newer generation tyrosine kinase inhibitors with increased potency against ROS1 and ROS1-resistance mutations, and improved intracranial activity are under evaluation in clinical trials. In this review, we discuss ROS1 rearrangements in non-small cell lung cancer, and provide an update on targeting ROS1-rearranged non-small cell lung cancer with crizotinib and newer generation tyrosine kinase inhibitors.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Crizotinibe/uso terapêutico , Rearranjo Gênico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Barreira Hematoencefálica/metabolismo , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Crizotinibe/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Terapia de Alvo Molecular , Mutação , Permeabilidade , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética
4.
Eur J Med Chem ; 179: 358-375, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260890

RESUMO

ALK and ROS1 kinases have become promising therapeutic targets since Crizotinib was used to treat non-small-cell lung cancer clinically. Aiming to explore new potent inhibitors, a series of 2-amino-4-(1-piperidine) pyridine derivatives that stabilized a novel DFG-shifted conformation in the kinase domain of ALK were designed and synthesized on the base of lead compound A. Biological evaluation highlighted that most of these new compounds could also potently inhibit ROS1 kinase, leading to the promising inhibitors against both ROS1 and ALK. Among them, the representative compound 2e stood out potent anti-proliferative activity against ALK-addicted H3122 and ROS1-addicted HCC78 cell lines (IC50 = 6.27 µM and 10.71 µM, respectively), which were comparable to that of Crizotinib. Moreover, 2e showed impressive enzyme activity against clinically Crizotinib-resistant ALKL1196M with an IC50 value of 41.3 nM, which was about 2-fold more potent than that of Crizotinib. 2e also showed potent inhibitory activity in about 6-fold superior to Crizotinib (IC50: 104.7 nM vs. 643.5 nM) in Ba/F3 cell line harboring ROS1G2032R. Furthermore, molecular modeling disclosed that all the representative inhibitors could dock into the active site of ALK and ROS1, which gave a probable explanation of anti Crizotinib-resistant mutants. These results indicated that our work has established a path forward for the generation of anti Crizotinib-resistant ALK/ROS1 dual inhibitors.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/farmacologia , Crizotinibe/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Piridinas/farmacologia , Células A549 , Quinase do Linfoma Anaplásico/metabolismo , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Crizotinibe/química , Relação Dose-Resposta a Droga , Desenho de Drogas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Piperidinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Piridinas/química , Relação Estrutura-Atividade
5.
N Engl J Med ; 381(4): 338-348, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31340094

RESUMO

BACKGROUND: Alterations in the gene encoding fibroblast growth factor receptor (FGFR) are common in urothelial carcinoma and may be associated with lower sensitivity to immune interventions. Erdafitinib, a tyrosine kinase inhibitor of FGFR1-4, has shown antitumor activity in preclinical models and in a phase 1 study involving patients with FGFR alterations. METHODS: In this open-label, phase 2 study, we enrolled patients who had locally advanced and unresectable or metastatic urothelial carcinoma with prespecified FGFR alterations. All the patients had a history of disease progression during or after at least one course of chemotherapy or within 12 months after neoadjuvant or adjuvant chemotherapy. Prior immunotherapy was allowed. We initially randomly assigned the patients to receive erdafitinib in either an intermittent or a continuous regimen in the dose-selection phase of the study. On the basis of an interim analysis, the starting dose was set at 8 mg per day in a continuous regimen (selected-regimen group), with provision for a pharmacodynamically guided dose escalation to 9 mg. The primary end point was the objective response rate. Key secondary end points included progression-free survival, duration of response, and overall survival. RESULTS: A total of 99 patients in the selected-regimen group received a median of five cycles of erdafitinib. Of these patients, 43% had received at least two previous courses of treatment, 79% had visceral metastases, and 53% had a creatinine clearance of less than 60 ml per minute. The rate of confirmed response to erdafitinib therapy was 40% (3% with a complete response and 37% with a partial response). Among the 22 patients who had undergone previous immunotherapy, the confirmed response rate was 59%. The median duration of progression-free survival was 5.5 months, and the median duration of overall survival was 13.8 months. Treatment-related adverse events of grade 3 or higher, which were managed mainly by dose adjustments, were reported in 46% of the patients; 13% of the patients discontinued treatment because of adverse events. There were no treatment-related deaths. CONCLUSIONS: The use of erdafitinib was associated with an objective tumor response in 40% of previously treated patients who had locally advanced and unresectable or metastatic urothelial carcinoma with FGFR alterations. Treatment-related grade 3 or higher adverse events were reported in nearly half the patients. (Funded by Janssen Research and Development; BLC2001 ClinicalTrials.gov number, NCT02365597.).


Assuntos
Antineoplásicos/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirazóis/administração & dosagem , Quinoxalinas/administração & dosagem , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/genética , Neoplasias Urológicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica/tratamento farmacológico , Intervalo Livre de Progressão , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/efeitos adversos , Quinoxalinas/efeitos adversos , Resultado do Tratamento , Neoplasias Urológicas/genética , Neoplasias Urológicas/patologia , Urotélio
6.
Cell Prolif ; 52(5): e12656, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31264309

RESUMO

OBJECTIVES: Cell migration has a key role in cancer metastasis, which contributes to drug resistance and tumour recurrence. Better understanding of the mechanisms involved in this process will potentially reveal new drug targets for cancer therapy. Fer is a non-receptor protein tyrosine kinase aberrantly expressed in various human cancers, whereas its role in tumour progression remains elusive. MATERIALS AND METHODS: Transgenic flies and epigenetic analysis were employed to investigate the role of Drosophila Fer (FER) in cell migration and underlying mechanisms. Co-immunoprecipitation assay was used to monitor the interaction between FER and Drosophila JNK (Bsk). The conservation of Fer in regulating JNK signalling was explored in mammalian cancer and non-cancer cells. RESULTS: Overexpression of FER triggered cell migration and activated JNK signalling in the Drosophila wing disc. Upregulation and downregulation in the basal activity of Bsk exacerbated and eliminated FER-mediated migration, respectively. In addition, loss of FER blocked signal transduction of the JNK pathway. Specifically, FER interacted with and promoted the activity of Bsk, which required both the kinase domain and the C-terminal of Bsk. Lastly, Fer regulated JNK activities in mammalian cells. CONCLUSIONS: Our study reveals FER as a positive regulator of JNK-mediated cell migration and suggests its potential role as a therapeutic target for cancer metastasis.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteínas Tirosina Quinases/metabolismo , Animais , Animais Geneticamente Modificados/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proteínas de Drosophila/química , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/química , Metaloproteinase 1 da Matriz/metabolismo , Domínios Proteicos , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Interferência de RNA , RNA Interferente Pequeno , Transdução de Sinais , Asas de Animais/metabolismo
7.
Medicine (Baltimore) ; 98(23): e15806, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31169681

RESUMO

BACKGROUND: Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) have been developed for targeted therapies in non-small-cell lung cancer (NSCLC); moreover, some drug-related toxic reactions among cancer patients have been reported. A meta-analysis of randomized controlled trials (RCTs) to definite the incidence and the risk of grade ≥3 adverse events (AEs), serious and fatal AEs (SAEs and FAEs), with VEGFR-TKIs in advanced/metastatic NSCLC patients was performed. METHODS: A comprehensive literature search was conducted for the clinical trials published up to December 2017. Qualified studies allotted patients with advanced/metastatic NSCLC to receive either chemotherapy alone or in combination with VEGFR-TKIs. Data were extracted by 2 authors. RESULTS: Eighteen RCTs of VEGFR-TKIs plus chemotherapy, involving 8461 advanced NSCLC patients were included. The proportion of patients with grade ≥3 AEs was increased with the addition of VEGFR-TKIs (relative risk, 1.35; 95% confidence interval [CI] 1.19-1.52; incidence, 68.1% vs 50.1%; P < .001). The most common grade ≥3 AEs was neutropenia (24.9% vs 15.4%, P < .001). Addition of VEGFR-TKIs was also related to the increased risk of SAEs (relative risk, 1.34; 95% CI 1.14-1.56; incidence, 37.8% vs 27.9%; P < .001) and FAEs (relative risk, 2.16, 95% CI 1.47-3.19; incidence, 3.4% vs 1.8%). Subgroup analysis suggested there was no difference in the rates of SAEs and FAEs in the second-line settings. No evidence of bias was found between the literatures. The study was registered with PROSPERO (CRD42018099654). CONCLUSIONS: In comparison with chemotherapy alone, the addition of VEGFR-TKIs in advanced NSCLC patients was related to the increased risk of grades ≥3 AEs, SAEs, and FAEs, especially in the first-line settings. Physicians should be aware of some specific grade ≥3 adverse effect, especially haematologic adverse events, and it is also necessary to monitor cancer patients receiving VEGFR-TKIs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
8.
Crit Rev Oncol Hematol ; 141: 23-35, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31202955

RESUMO

Recently, tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICPIs) have emerged as new classes of anticancer therapies. Although generally considered less toxic than cytotoxic chemotherapy, these new drugs can cause significant unanticipated side effects including thyroid dysfunction. This review provides a literature assessment of thyroid dysfunctions induced by TKI and ICPIs. We intend to define for these two classes the frequency of thyroid involvement, the potential mechanisms that result in this toxicity, the clinical-biological impact and the therapeutic management. Detection of thyroid dysfunction requires monitoring of TSH, in combination with free T4 if needed and, depending on the clinical impact and the kinetics of biological abnormalities, starting symptomatic treatment of hyperthyroidism and/or correcting hypothyroidism.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Tirosina Quinases/antagonistas & inibidores , Doenças da Glândula Tireoide/induzido quimicamente , Antineoplásicos Imunológicos/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/imunologia , Humanos , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/diagnóstico , Hipotireoidismo/patologia , Hipotireoidismo/terapia , Neoplasias/fisiopatologia , Inibidores de Proteínas Quinases/uso terapêutico , Doenças da Glândula Tireoide/diagnóstico , Doenças da Glândula Tireoide/patologia , Doenças da Glândula Tireoide/terapia , Testes de Função Tireóidea
9.
Leukemia ; 33(8): 1835-1850, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31209280

RESUMO

Outcomes for patients with chronic myeloid leukemia (CML) have substantially improved due to advances in drug development and rational treatment intervention strategies. Despite these significant advances there are still unanswered questions on patient management regarding how to more reliably predict treatment failure at the time of diagnosis and how to select frontline tyrosine kinase inhibitor (TKI) therapy for optimal outcome. The BCR-ABL1 transcript level at diagnosis has no established prognostic impact and cannot guide frontline TKI selection. BCR-ABL1 mutations are detected in ~50% of TKI resistant patients but are rarely responsible for primary resistance. Other resistance mechanisms are largely uncharacterized and there are no other routine molecular testing strategies to facilitate the evaluation and further stratification of TKI resistance. Advances in next-generation sequencing technology has aided the management of a growing number of other malignancies, enabling the incorporation of somatic mutation profiles in diagnosis, classification, and prognostication. A largely unexplored area in CML research is whether expanded genomic analysis at diagnosis, resistance, and disease transformation can enhance patient management decisions, as has occurred for other cancers. The aim of this article is to review publications that reported mutated cancer-associated genes in CML patients at various disease phases. We discuss the frequency and type of such variants at initial diagnosis and at the time of treatment failure and transformation. Current limitations in the evaluation of mutants and recommendations for future reporting are outlined. The collective evaluation of mutational studies over more than a decade suggests a limited set of cancer-associated genes are indeed recurrently mutated in CML and some at a relatively high frequency. Genomic studies have the potential to lay the foundation for improved diagnostic risk classification according to clinical and genomic risk, and to enable more precise early identification of TKI resistance.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Genes Neoplásicos , Hematopoese , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/etiologia , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Repressoras/genética , Medição de Risco
10.
Rinsho Shinkeigaku ; 59(7): 418-424, 2019 Jul 31.
Artigo em Japonês | MEDLINE | ID: mdl-31243247

RESUMO

A 76-year-old man, diagnosed with chronic myeloid leukemia in 2010, had been on nilotinib for 7 years. He presented with right hemiparesis in September 2017. He had no history of hypertension, diabetes, hyperlipidemia, heart disease, or smoking. Brain MRI revealed a border-zone infarction of the left cerebral hemisphere and a rapidly progressing severe left internal carotid artery (ICA) stenosis. He was initiated on clopidogrel and bosutinib instead of nilotinib. He presented with right hemiparesis once again in December 2017. Brain MRI revealed the border-zone infarction of the left cerebral hemisphere and a more progressed, severe bilateral ICA stenosis. A carotid ultrasound demonstrated iso-intense and concentrically narrowed ICA on both sides. Carotid artery stenting of the left ICA was performed in February 2018, and clopidogrel was replaced by cilostazol to provide a drug-induced rush. Carotid artery stenting of the right ICA was performed in June 2018 and cervical angiogram demonstrated that there were no residual artery stenoses in the bilateral stent. In recent years, several case reports suggest that tyrosine kinase inhibitors (TKIs) are associated with progressive artery stenosis and cause cerebral infarction. Brain imaging tests should be conducted to evaluate arterial stenosis progression for patients with a history of taking TKI when an arterial vascular event occurs.


Assuntos
Compostos de Anilina/administração & dosagem , Compostos de Anilina/efeitos adversos , Infarto Cerebral/induzido quimicamente , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Nitrilos/administração & dosagem , Nitrilos/efeitos adversos , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Administração Oral , Idoso , Artéria Carótida Interna , Estenose das Carótidas/induzido quimicamente , Estenose das Carótidas/cirurgia , Infarto Cerebral/diagnóstico por imagem , Clopidogrel/administração & dosagem , Imagem de Difusão por Ressonância Magnética , Humanos , Masculino , Recidiva , Stents
11.
Eur J Med Chem ; 175: 247-268, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31121430

RESUMO

As a dual-specificity protein kinase, monopolar spindle 1 (Mps1) is one of the main kinases involved in kinetochore localization and the spindle assembly checkpoint (SAC). Cancer cells often display chromosomal instability, which is a consequence of disfunction of cell cycle checkpoints partially. Mps1 is overexpressed in multiple cancer types to face the pressure from aberrant chromosomes and centrosomes. Therefore, Mps1 is a potential targeting approach to cancer treatment. Several compounds targeting Mps1 have been developed and approved to begin clinical trials for advanced nonhaematologic malignancies treatments, including but not limited to triple negative breast cancer (TNBC) treatment. In this review, we will highlight typical Mps1 inhibitors developed during the last decade and provide a reference for more potential Mps1 inhibitors exploration in the future.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Desenho de Drogas , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Fuso Acromático/efeitos dos fármacos , Antineoplásicos/farmacocinética , Proteínas de Ciclo Celular/química , Resistência a Medicamentos , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Conformação Proteica , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/química , Proteínas Tirosina Quinases/química , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/patologia
12.
Drugs Today (Barc) ; 55(4): 231-236, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31050691

RESUMO

Dacomitinib (PF-00299804, Vizimpro) was developed as a second-generation, oral, irreversible inhibitor of human epidermal growth factor receptor (EGFR)- 1, -2 and -4 tyrosine kinase. On September 27, 2018, the United States Food and Drug Administration (FDA) approved dacomitinib for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletion or exon 21 L858R substitution mutations. On January 8, 2019, the Ministry of Health, Labour and Welfare of Japan approved this second-generation EGFR tyrosine kinase inhibitor (TKI) for the treatment of EGFR mutation-positive inoperable or recurrent NSCLC. The European Commission also approved dacomitinib on April 3, 2019, as monotherapy for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR activating mutations. Approval of dacomitinib was based on a randomized, multicenter, open-label, active-controlled trial (ARCHER 1050; ClinicalTrials.gov Identifier NCT01774721) which demonstrated the safety and efficacy of dacomitinib compared to gefitinib in 452 patients with unresectable and metastatic NSCLC. Dacomitinib represents a powerful new treatment option compared with first-generation EGFR-TKIs. In this paper, we review the clinical and preclinical studies of dacomitinib and discuss the drug's clinical value.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinonas/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Humanos , Mutação , Recidiva Local de Neoplasia , Proteínas Tirosina Quinases/antagonistas & inibidores , Ensaios Clínicos Controlados Aleatórios como Assunto
13.
Drugs ; 79(8): 887-891, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31093950

RESUMO

Peficitinib [Smyraf® (Astellas Pharma)] is a Janus kinase (JAK)1, JAK2, JAK3 and tyrosine kinase (Tyk)2 (pan-JAK) inhibitor recently approved in Japan for the treatment of rheumatoid arthritis. Inhibition of JAK suppresses the activation of cytokine signalling pathways involved in inflammation and joint destruction in rheumatoid arthritis. Peficitinib has been shown to significantly improve ACR20 and other measures of disease severity and to reduce the mean modified total Sharp score change from baseline in clinical trials. This article summarizes the milestones in the development of peficitinib leading to this first approval as a treatment for rheumatoid arthritis in patients who have an inadequate response to conventional therapies.


Assuntos
Adamantano/análogos & derivados , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Niacinamida/análogos & derivados , Inibidores de Proteínas Quinases/uso terapêutico , Adamantano/farmacologia , Adamantano/uso terapêutico , Antirreumáticos/farmacologia , Aprovação de Drogas , Humanos , Janus Quinases/antagonistas & inibidores , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores
15.
N Engl J Med ; 380(26): 2518-2528, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31112379

RESUMO

BACKGROUND: Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis and a leading cause of systemic sclerosis-related death. Nintedanib, a tyrosine kinase inhibitor, has been shown to have antifibrotic and antiinflammatory effects in preclinical models of systemic sclerosis and ILD. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of nintedanib in patients with ILD associated with systemic sclerosis. Patients who had systemic sclerosis with an onset of the first non-Raynaud's symptom within the past 7 years and a high-resolution computed tomographic scan that showed fibrosis affecting at least 10% of the lungs were randomly assigned, in a 1:1 ratio, to receive 150 mg of nintedanib, administered orally twice daily, or placebo. The primary end point was the annual rate of decline in forced vital capacity (FVC), assessed over a 52-week period. Key secondary end points were absolute changes from baseline in the modified Rodnan skin score and in the total score on the St. George's Respiratory Questionnaire (SGRQ) at week 52. RESULTS: A total of 576 patients received at least one dose of nintedanib or placebo; 51.9% had diffuse cutaneous systemic sclerosis, and 48.4% were receiving mycophenolate at baseline. In the primary end-point analysis, the adjusted annual rate of change in FVC was -52.4 ml per year in the nintedanib group and -93.3 ml per year in the placebo group (difference, 41.0 ml per year; 95% confidence interval [CI], 2.9 to 79.0; P = 0.04). Sensitivity analyses based on multiple imputation for missing data yielded P values for the primary end point ranging from 0.06 to 0.10. The change from baseline in the modified Rodnan skin score and the total score on the SGRQ at week 52 did not differ significantly between the trial groups, with differences of -0.21 (95% CI, -0.94 to 0.53; P = 0.58) and 1.69 (95% CI, -0.73 to 4.12 [not adjusted for multiple comparisons]), respectively. Diarrhea, the most common adverse event, was reported in 75.7% of the patients in the nintedanib group and in 31.6% of those in the placebo group. CONCLUSIONS: Among patients with ILD associated with systemic sclerosis, the annual rate of decline in FVC was lower with nintedanib than with placebo; no clinical benefit of nintedanib was observed for other manifestations of systemic sclerosis. The adverse-event profile of nintedanib observed in this trial was similar to that observed in patients with idiopathic pulmonary fibrosis; gastrointestinal adverse events, including diarrhea, were more common with nintedanib than with placebo. (Funded by Boehringer Ingelheim; SENSCIS ClinicalTrials.gov number, NCT02597933.).


Assuntos
Inibidores Enzimáticos/uso terapêutico , Indóis/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , Escleroderma Sistêmico/complicações , Administração Oral , Adulto , Diarreia/induzido quimicamente , Progressão da Doença , Método Duplo-Cego , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Indóis/efeitos adversos , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/tratamento farmacológico , Capacidade Vital
16.
Mol Med Rep ; 19(6): 5219-5226, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059042

RESUMO

Feline sarcoma­related protein (Fer) is a type of nuclear and cytoplasmic non­receptor protein tyrosine kinase, which is associated with the progression of numerous types of cancer. Previously, we identified that Fer is associated with the migration and invasion of bladder cancer. The present study aimed to investigate the role of Fer in bladder cancer cell viability and apoptosis. Reverse transcription­quantitative polymerase chain reaction and western blot analysis were performed to detect the expression levels of Fer; short interference RNA (siRNA) and overexpression vectors were used to downregulate or upregulate Fer expression, respectively. The effects on cell proliferation ability and cell apoptosis were then tested by MTT assay and flow cytometry. The results revealed that Fer expression was upregulated in bladder cancer cell lines. Downregulation of Fer expression by siRNA significantly suppressed T24 cell viability and induced apoptosis, as well as inducing cell cycle arrest. Conversely, Fer overexpression in 5637 cells significantly promoted cell viability and cell cycle progression, but inhibited cell apoptosis. Furthermore, the suppression and overexpression of Fer significantly altered the expression of cleaved caspase­3 and Bcl­2, and dysregulated the P38 mitogen­activated protein kinase signaling pathway. The findings of the present study indicate a possible molecular mechanism of Fer in bladder cancer and may be considered as a potential target in the treatment of this disease.


Assuntos
Proteínas Tirosina Quinases/metabolismo , Apoptose , Caspase 3/metabolismo , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Regulação para Baixo , Humanos , Sistema de Sinalização das MAP Quinases , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Regulação para Cima , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
17.
Molecules ; 24(7)2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30939771

RESUMO

Despite their side effects, cholinesterase (ChE) inhibitors remain the only approved drugs to treat Alzheimer's disease patients, along with the N-methyl-d-aspartate (NMDA) receptor antagonist memantine. In the last few years, the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) has also been studied as a promising target for the development of new drugs for this pathology. In this context, and based on our previous characterization of bio-oxidizable prodrugs of potent acetylcholinesterase (AChE) inhibitors, we envisioned a strategy involving the synthesis of a bio-oxidizable prodrug of both ChE and DYRK1A inhibitors. To this end, we fixed our interest on a known potent inhibitor of DYRK1A, namely INDY. The designed prodrug of both ChE and DYRK1A inhibitors was successfully synthesized, connecting both inhibitors by a carbonate link. This prodrug and its corresponding drug were then evaluated as ChEs and DYRK1A inhibitors. Remarkably, in vitro results were in accordance with the starting hypothesis, showing a relative inactivity of the prodrug against DYRK1A and ChEs and a potent inhibition of ChEs by the oxidized form. Molecular docking and kinetic studies of ChE inhibition by the active compound are also discussed in this report.


Assuntos
Acetilcolinesterase/química , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Desenho de Drogas , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Inibidores da Colinesterase/química , Humanos , Técnicas In Vitro , Cinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Conformação Proteica
18.
Medicine (Baltimore) ; 98(15): e15222, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30985724

RESUMO

To investigate the association of 3- and 6-month BCR-ABL transcript levels on the international scale (BCR-ABL) and other factors with deep molecular response (DMR) achievement in chronic myeloid leukemia (CML)-chronic phase (CP) patients receiving tyrosine kinase inhibitor (TKI) therapy.We retrospectively analyzed the clinical data of 206 patients enrolled in our hospital between January 2010 and July 2018. These patients were initially diagnosed with CML-CP and received imatinib or nilotinib therapy. Early molecular response (EMR) was assessed based on BCR-ABL (IS: on the international scale) transcript level at 3 and 6 months. Potential factors impacting DMR achievement were identified using Cox proportional hazard regression models. The effects of EMR achievement on the cumulative incidence of MR4.0 were investigated via Kaplan-Meier analysis.Multivariate Cox regression analysis showed that a BCR-ABL transcript level at 3 and 6 months of TKI therapy was an independent factor for the achievement of MR4.0, which was nevertheless not related to age, gender, Sokal score, hemoglobin level, or white blood cell (WBC) count at the initial time of diagnosis. Patients achieving an EMR (EMR: 3-month BCR-ABL ≤10%, 6-month BCR-ABL <1%) were more likely to reach MR4.0 than patients failing to achieve EMR (P1 <.001, P2 <.001). Patients who had 3-month BCR-ABL ≤1% were more likely to reach MR4.0 than those who had 3-month BCR-ABL of 1% to 10% or >10% (P1 = .001, P2 <.001). Similarly, patients who had 6-month BCR-ABL ≤0.1% were more likely to achieve MR4.0 than those in the 0.1% to 1% and ≥1% groups (P1 <.001, P2 <.001). Also, a higher percentage of patients on nilotinib therapy achieved EMR compared with patients on imatinib therapy (93.3% vs 63.6% on 3-month nilotinib therapy, P = .001; 88.9% vs 59.9% on 6-month nilotinib therapy, P = .004).This study demonstrates that EMR, especially a 3-month BCR-ABL ≤1% and 6-month BCR-ABL ≤0.1%, have predictive value for DMR achievement. In addition, there is a higher percentage of patients receiving nilotinib therapy achieved EMR than that of those receiving imatinib therapy.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Adulto , Biomarcadores Tumorais/metabolismo , Doença Crônica , Feminino , Seguimentos , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prognóstico , Pirimidinas/uso terapêutico , Estudos Retrospectivos , Fatores de Tempo , Transcrição Genética
19.
Eur J Med Chem ; 173: 167-183, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30999237

RESUMO

Interleukin-2-inducible T-cell kinase (Itk) plays an important role in multiple signal transduction pathways in T and mast cells, and is a potential drug target for treating inflammatory diseases, autoimmune diseases, and T cell leukemia/lymphoma. Herein, we describe the discovery of a series of covalent Itk inhibitors based on the 7H-pyrrolo[2,3-d]pyrimidine scaffold. Placing an appropriate substitution group at a hydration site of the ATP binding pocket of Itk and using a saturated heterocyclic ring as a linker to the reactive group were crucial for selectivity. The optimized compound 9 showed potent activity against Itk, excellent selectivity for Itk over Btk and other structurally related kinases, inhibition of phospholipase C-γ1 (PLC-γ1) phosphorylation in cells, and anti-proliferative effects against multiple T leukemia/lymphoma cell lines. Compound 9 can serve as a valuable compound for further determination of functions of Itk.


Assuntos
Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Células Jurkat , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/síntese química , Pirimidinas/química , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
20.
Curr Med Sci ; 39(2): 211-216, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31016512

RESUMO

Discontinuation of tyrosine kinase inhibitor (TKI) therapy after achieving a persistent deep molecular response (DMR) is an urgently needed treatment goal for chronic myeloid leukemia (CML) patients and has been included in the National Comprehensive Cancer Network (NCCN) guidelines (version 2.2017) for CML. Indeed, various studies have confirmed the feasibility of discontinuing TKI therapy. In this study, we analyzed data from 45 CML patients who had discontinued TKI therapy. Univariate analysis was performed to predict factors that were potentially related to treatment-free remission (TFR) and identify the differences between early relapse and late relapse. Out of the 45 patients, 20 exhibited molecular relapse after a median follow-up of 18 months (range, 1-54 months), and the estimated TFR at 24 months was 40%. The univariate analysis revealed that a high Sokal score and interruptions or dose reductions during TKI treatment were the only baseline factors associated with poor outcomes. Our results indicate that TKI discontinuation could be successfully put into practice in China.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Adolescente , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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