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1.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-33802972

RESUMEN

Leukaemia is a malignant disease of the blood. Current treatments for leukaemia are associated with serious side-effects. Plant-derived polyphenols have been identified as potent anti-cancer agents and have been shown to work synergistically with standard chemotherapy agents in leukaemia cell lines. Polyphenols have multiple mechanisms of action and have been reported to decrease cell proliferation, arrest cell cycle and induce apoptosis via the activation of caspase (3, 8 and 9); the loss of mitochondrial membrane potential and the release of cytochrome c. Polyphenols have been shown to suppress activation of transcription factors, including NF-kB and STAT3. Furthermore, polyphenols have pro-oxidant properties, with increasing evidence that polyphenols inhibit the antioxidant activity of glutathione, causing oxidative DNA damage. Polyphenols also induce autophagy-driven cancer cell death and regulate multidrug resistance proteins, and thus may be able to reverse resistance to chemotherapy agents. This review examines the molecular mechanism of action of polyphenols and discusses their potential therapeutic targets. Here, we discuss the pharmacological properties of polyphenols, including their anti-inflammatory, antioxidant, anti-proliferative, and anti-tumour activities, and suggest that polyphenols are potent natural agents that can be useful therapeutically; and discuss why data on bioavailability, toxicity and metabolism are essential to evaluate their clinical use.


Asunto(s)
Leucemia/tratamiento farmacológico , Polifenoles/uso terapéutico , Animales , Autofagia/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Humanos , Leucemia/patología , Modelos Biológicos , Polifenoles/química , Polifenoles/farmacología , Especies Reactivas de Oxígeno/metabolismo
2.
Nat Commun ; 12(1): 1850, 2021 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-33767176

RESUMEN

Artificial intelligence and machine learning (ML) promise to transform cancer therapies by accurately predicting the most appropriate therapies to treat individual patients. Here, we present an approach, named Drug Ranking Using ML (DRUML), which uses omics data to produce ordered lists of >400 drugs based on their anti-proliferative efficacy in cancer cells. To reduce noise and increase predictive robustness, instead of individual features, DRUML uses internally normalized distance metrics of drug response as features for ML model generation. DRUML is trained using in-house proteomics and phosphoproteomics data derived from 48 cell lines, and it is verified with data comprised of 53 cellular models from 12 independent laboratories. We show that DRUML predicts drug responses in independent verification datasets with low error (mean squared error < 0.1 and mean Spearman's rank 0.7). In addition, we demonstrate that DRUML predictions of cytarabine sensitivity in clinical leukemia samples are prognostic of patient survival (Log rank p < 0.005). Our results indicate that DRUML accurately ranks anti-cancer drugs by their efficacy across a wide range of pathologies.


Asunto(s)
Antineoplásicos/uso terapéutico , Biología Computacional/métodos , Citarabina/uso terapéutico , Ensayos de Selección de Medicamentos Antitumorales/métodos , Leucemia/tratamiento farmacológico , Aprendizaje Automático , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Hep G2 , Humanos , Leucemia/mortalidad , Neoplasias/tratamiento farmacológico , Pronóstico , Proteómica/métodos
3.
Ciudad Autónoma de Buenos Aires; Comisión Nacional de Evaluación de Tecnologías de Salud; Marzo 2021. 30 p. (Informe de Evaluación de Tecnologías Sanitarias N°15, 15).
Monografía en Español | LILACS, BINACIS, ARGMSAL | ID: biblio-1151674

RESUMEN

El presente informe es producto del trabajo colaborativo de la Comisión Nacional de Evaluación de Tecnologías de Salud (CONETEC), dependiente del Ministerio de Salud de la Nación y creada por RM N° 623/2018. La CONETEC realiza evaluaciones y emite recomendaciones a la autoridad sanitaria sobre la incorporación, forma de uso, financiamiento y políticas de cobertura de las tecnologías sanitarias desde una perspectiva global del sistema de salud argentino. En sus evaluaciones y recomendaciones, la CONETEC tiene en cuenta criterios de calidad, seguridad, efectividad, eficiencia y equidad, evaluados bajo dimensiones éticas, médicas, económicas y sociales. Sus resultados son consensuados mediante discusiones públicas y ponderados a través de un marco de valor explícito, con la participación de todos los actores involucrados en el proceso de toma de decisiones en salud. Los informes y recomendaciones de esta comisión surgen de este proceso público, transparente y colaborativo, siendo de libre consulta y acceso para toda la sociedad.


Asunto(s)
Anciano , Leucemia/tratamiento farmacológico , Leucemia/epidemiología
4.
Int J Mol Sci ; 22(2)2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33467555

RESUMEN

Acute leukemias, the most common cancers in children, are characterized by excessive proliferation of malignant progenitor cells. As a consequence of impaired blood cell production, leukemia patients are susceptible to infectious complications-a major cause of non-relapse mortality. Neutrophil extracellular traps (NETs) are involved in various pathologies, from autoimmunity to cancer. Although aberrant NETs formation may be partially responsible for immune defects observed in acute leukemia, still little is known on the NET release in the course of leukemia. Here, we present the first comprehensive evaluation of NETs formation by neutrophils isolated from children with acute leukemia in different stages of the disease and treatment stimulated in vitro with phorbol 12-myristate 13-acetate (PMA), N-formyl-methionyl-leucyl-phenylalanine (fMLP), and calcium ionophore (CI). NETs release was measured using quantitative fluorescent method and visualized microscopically. In this setting, NETs release was significantly impaired in leukemic children both at the diagnosis and during the treatment, and full restoration of neutrophil function was achieved only after successful completion of the leukemia treatment. We suggest that neutrophil function impairment may result from both disease- and treatment-related factors. In this context, deficient innate immune response observed in acute leukemia patients may be present regardless of neutrophil count and contribute to secondary immunodeficiency observed in this population.


Asunto(s)
Trampas Extracelulares/inmunología , Inmunidad Innata/inmunología , Leucemia/inmunología , Neutrófilos/inmunología , Enfermedad Aguda , Adolescente , Ionóforos de Calcio/farmacología , Células Cultivadas , Niño , Preescolar , Humanos , Inmunidad Innata/efectos de los fármacos , Lactante , Leucemia/sangre , Leucemia/tratamiento farmacológico , N-Formilmetionina Leucil-Fenilalanina/farmacología , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Acetato de Tetradecanoilforbol/farmacología
5.
Exp Hematol ; 94: 31-36, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33453340

RESUMEN

BAALC is identified as a leukemia-associated gene and is highly expressed in CD34-positive hematopoietic stem cells. High BAALC expression is associated with poor prognosis in several types of acute myeloid leukemia. We explored binding partner proteins of BAALC by means of mass spectrometry and analyzed biological properties of BAALC-expressing leukemic cells. We found that BAALC physically interacts with DBN1, which is an actin-binding protein and promotes cell adhesion and mobility by forming cell membrane spines during cell-cell interactions. Drebrin1 downregulation impeded cell adhesion to bone marrow stromal cells, resulting in improvement of sensitivity to cytarabine. Taken together, our findings suggest that BAALC-DBN1 interaction contributes to the anchoring of BAALC-expressing cells in the bone marrow, which in turn leads to resistance to cytotoxic drugs. Therefore, the BAALC-DBN1 interaction provides us with an opportunity to overcome the chemotherapy resistance in BAALC-activated leukemia via functional blockage of these genes.


Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Citarabina/farmacología , Resistencia a Antineoplásicos , Leucemia/tratamiento farmacológico , Proteínas de Neoplasias/metabolismo , Neuropéptidos/metabolismo , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Células Jurkat , Leucemia/genética , Leucemia/metabolismo , Proteínas de Neoplasias/genética , Neuropéptidos/genética , Mapas de Interacción de Proteínas/efectos de los fármacos
6.
Phytomedicine ; 80: 153383, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33091855

RESUMEN

BACKGROUND: Caffeic acid 3,4-dihydroxyphenethyl ester (CADPE) is a natural polyphenolic ester isolated as a minor component from a water extract of the Chinese medicine Zhongjiefeng [Sarcandra glabra (Thunb.) Nakai (Chloranthaceae)] and has previously shown to have activity against solid tumors through the modulation of multiple targets or signal pathways. However, the activity and potential mechanism of CADPE against leukemia cells have not yet been characterized. PURPOSE: To investigate whether and how CADPE kills leukemia cells. METHOD: (1) The activity of CADPE inhibiting the growth of different leukemia cell lines was evaluated by MTT assay; (2) Cell cycle arrest and apoptosis induced by CADPE were determined by flow cytometry with FlowJo software for quantification; (3) The protein levels were analyzed by Western blot and ubiquitin-binding c-Myc was acquired by co-immunoprecipitation. RESULTS: CADPE exerted potent activity against different leukemia cell lines with low toxicity in normal cells. In terms of mechanism of action, CADPE promoted ubiquitin-proteasome-dependent degradation of c-Myc through activating glycogen synthase kinase-3ß (GSK3ß) and downregulating deubiquitinating enzyme USP28 to trigger the interaction of c-Myc with ubiquitin ligase Fbw7, resulting in the downregulation of cell cycle regulators and anti-apoptotic proteins and consequently, cell cycle arrest and cell apoptosis. CONCLUSION: CADPE is a novel c-Myc inhibitor with high activity and a unique mechanism for killing leukemia cells.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Ácidos Cafeicos/farmacología , Leucemia/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proteínas F-Box/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Leucemia/metabolismo , Leucemia/patología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Transducción de Señal/efectos de los fármacos , Ubiquitina/metabolismo , Ubiquitina Tiolesterasa/metabolismo
9.
Phytomedicine ; 81: 153409, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33341310

RESUMEN

BACKGROUND: Sesquiterpene lactones having α-methylene-γ-lactone moiety are promising natural metabolites showing various biological activity. One of the major metabolites isolated from Pulicaria undulata, 2α-hydroxyalantolactone (PU-1), has not been investigated in detail yet. Multidrug resistance (MDR) represents a major obstacle for cancer chemotherapy and the capability of novel natural products to overcoming MDR is of great interest. PURPOSE: Exploring the molecular modes of action for potent natural product metabolites. METHODS: The resazurin reduction assay was employed to evaluate the cytotoxicity of PU-1 on sensitive and their corresponding drug-resistant cell lines (overexpressing P-glycoprotein, BCRP, ABCB5, ΔEGFR, or TP53 knockout). Gene expression profiling was performed by transcriptome-wide mRNA microarray in the human CCRF-CEM leukemic cells after treatment with PU-1. The top significantly up- or down-regulated genes were identified by Chipster program and analyzed using Ingenuity Pathway Analysis (IPA) software. Finally, flow cytometry and Western blotting were performed for cell cycle analyses and apoptosis detection. RESULTS: The sesquiterpene lactone, PU-1, showed potent cytotoxicity towards the drug-sensitive and -resistant cell lines. Transcriptome-wide mRNA expression profiling and pathway analysis pointed to genes involved in DNA damage response and G2/M cell cycle arrest. G2/M arrest was verified by flow cytometry and further confirmed by the upregulation of p21 and downregulation of p-CDC25C expression in Western blotting. Moreover, the suggested DNA damage checkpoint regulation was confirmed by immunofluorescence and Western blotting by upregulation of pS345 Chk1, p-H3 and γ-H2AX. Furthermore, PU-1 inhibited PI3K/AKT pathway, which is involved in signaling DNA damage and G2/M arrest. Cells ultimately induced apoptosis upon PU-1 treatment. CONCLUSIONS: PU-1 is a potent natural product inhibiting otherwise drug-resistant human tumor cell growth through DNA damage, G2/M cell cycle arrest and apoptosis.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia/tratamiento farmacológico , Pulicaria/química , Sesquiterpenos/farmacología , Antineoplásicos Fitogénicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , Resistencia a Antineoplásicos/fisiología , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Leucemia/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Sesquiterpenos/química
10.
J Ethnopharmacol ; 266: 113458, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33039632

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Fumaria officinalis (Fumariaceae) is recorded in the Kurdish ethnobotany for various health problems. AIM OF THE STUDY: In this study, the cytotoxic activity of F. officinalis extracts on two leukemia and nine multiple myeloma (MM) cell lines was investigated. MATERIALS AND METHODS: The cytotoxic and ferroptotic activity were examined by resazurin reduction assay. Flow cytometry, immunoblotting assay and fluorescence microscopy were used to measure cell cycle distribution, apoptosis, induction of reactive oxygen species (ROS), loss integrity of mitochondrial membrane potential (MMP) and autophagy. LC-ESI/MS was used to identify chemical constituents present in F. officinalis. RESULTS: Chloroform (CF) and ethyl acetate (EF) fractions showed drastic cytotoxic effect on CCRF-CEM and CEM/ADR 5000 cells. NCI-H929 cell line exhibited higher sensitivity against CF, while EF demonstrated its higher cytotoxicity on OPM-2 cells with IC50 value 14.80 ± 1.70 and 28.13 ± 1.38 µg/mL respectively. Flow cytometric and morphological studies confirmed that CF and EF induced apoptosis in NCI-H929 cells by loss of MMP, generation of ROS and obvious morphological variations. In DNA histograms, up to 50% of the cells were accumulated by CF and 44% by EF in the sub-G0/G1 phase following 72 h treatment. EF induced autophagic cell death, while CF stimulated iron-dependent cell death. Moreover, two isoquinoline alkaloids and four flavonoids were identified in the active fractions. CONCLUSION: To our knowledge, this is the first report demonstrating the cytotoxicity of F. officinalis extracts in MM cell lines. CF and EF fractions inhibited MM cell proliferation through various modes of actions.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Fumaria/química , Leucemia/tratamiento farmacológico , Mieloma Múltiple/tratamiento farmacológico , Extractos Vegetales/farmacología , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Humanos , Concentración 50 Inhibidora , Leucemia/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mieloma Múltiple/patología , Extractos Vegetales/administración & dosificación , Especies Reactivas de Oxígeno/metabolismo
11.
Eur J Med Chem ; 211: 113095, 2021 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-33360560

RESUMEN

Targeting epigenetic dysregulation has emerged as a valuable therapeutic strategy in cancer treatment. Especially epigenetic combination therapy of histone deacetylase inhibitors (HDACi) with established anti-cancer drugs has provided promising results in preclinical and clinical studies. The structural optimization of alkoxyamide-based class I/IIb inhibitors afforded improved analogs with potent efficacy in cisplatin-resistant head and neck carcinoma cells and bortezomib-resistant leukemia cells. The most promising HDACi showed a superior synergistic cytotoxic activity as compared to vorinostat and class I HDACi in combination with cisplatin, leading to a full reversal of the chemoresistant phenotype in head and neck cancer cell lines, as well in combination with the proteasome inhibitors (bortezomib and carfilzomib) in a panel of leukemic cell lines. Furthermore, the most valuable alkoxyamide-based HDACi exhibited strong ex vivo anticancer efficacy against primary patient samples obtained from different therapy-resistant leukemic entities.


Asunto(s)
Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Epigenómica/métodos , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/uso terapéutico , Leucemia/tratamiento farmacológico , Antineoplásicos/farmacología , Sinergismo Farmacológico , Neoplasias de Cabeza y Cuello/patología , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Leucemia/patología
12.
Int J Mol Sci ; 21(24)2020 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-33371413

RESUMEN

Guaiane-type sesquiterpene lactones are naturally occurring compounds which have attracted attention due to their array of biological activities. In this study, chlorinated guaianolides 1-8, isolated from plants of the genus Centaurea, were evaluated against the human leukemia cell lines HL-60, U-937, a specific U-937 cell line that overexpresses the anti-apoptotic Bcl-2 protein and the human melanoma cell line SK-MEL-1. This established the relevant structure-growth inhibition relationships. Chlorohyssopifolins A (1), C (3) and D (4) and linichlorin A (6) were the most potent compounds in terms of inducing growth inhibition in the four cell lines. IC50 values were below 10 µM in all cases. Chlorohyssopifolins A (1) and D (4) and linichlorin A (6) were potent apoptotic inducers in human U-937 leukemia cells, as determined by fluorescent microscopy and flow cytometry, and their mechanism of action was associated with cytochrome c release, caspase activation and poly(ADP-ribose)polymerase cleavage. Overall this study shows that guaianolides induce cytotoxicity against human tumor cells and provides important insights into the cell death pathways that are involved.


Asunto(s)
Antineoplásicos/farmacología , Citotoxinas/farmacología , Lactonas/farmacología , Leucemia/patología , Sesquiterpenos de Guayano/química , Apoptosis , Citocromos c/metabolismo , Humanos , Leucemia/tratamiento farmacológico , Poli(ADP-Ribosa) Polimerasas/metabolismo , Células U937
13.
Med. oral patol. oral cir. bucal (Internet) ; 25(6): e791-e798, nov. 2020. tab, graf
Artículo en Inglés | IBECS | ID: ibc-197188

RESUMEN

BACKGROUND: Oropharyngeal mucositis (OM) is one of the main side-effects of oncological therapy. There is no treatment to prevent its occurrence, but some zinc-based therapies have been proven to help in decreasing its in-tensity. The objective of this study was to determine the effect of zinc in OM in children with acute leukemia in the early stages of oncological treatment. MATERIAL AND METHODS: This quasi-experimental study evaluated OM in 2 groups (control group: conventional hospital management, and experimental group: administration of 50 mg of zinc gluconate daily plus conventional hospital management). OM severity was recorded at a two-month follow-up. RESULTS: Forty-nine patients (26 in the control group and 23 in the experimental group) were included. The mean age of the patients was 11.1 ± 2.7 years; 65.3% had a diagnosis of pre-B acute lymphoblastic leukemia. The incidences of OM in the control group and the experimental group were 46.2% and 26.1%, respectively, but the difference was not significant. Based on a negative binomial regression model, females had, on average, 1.5 more days with OM (p = 0.002), and patients assigned to the experimental group had, on average, 2 less days with OM than the control group (p = 0.001). The pain score was higher in the control group (p = 0.0009), as was the mean score on the WHO scale (p = 0.0012). CONCLUSIONS: Zinc facilitated a reduction in the severity and duration of OM; further studies focusing on children are needed to confirm the effects of this trace element


No disponible


Asunto(s)
Humanos , Masculino , Femenino , Niño , Adolescente , Leucemia/tratamiento farmacológico , Estomatitis/inducido químicamente , Estomatitis/tratamiento farmacológico , Zinc/uso terapéutico , Antineoplásicos/efectos adversos , Gluconatos/uso terapéutico , Leucemia/complicaciones , Resultado del Tratamiento , Índice de Severidad de la Enfermedad , Análisis de Varianza , Escala Visual Analógica
14.
Med Oral Patol Oral Cir Bucal ; 25(6): e791-e798, 2020 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-33037810

RESUMEN

BACKGROUND: Oropharyngeal mucositis (OM) is one of the main side-effects of oncological therapy. There is no treatment to prevent its occurrence, but some zinc-based therapies have been proven to help in decreasing its intensity. The objective of this study was to determine the effect of zinc in OM in children with acute leukemia in the early stages of oncological treatment. MATERIAL AND METHODS: This quasi-experimental study evaluated OM in 2 groups (control group: conventional hospital management, and experimental group: administration of 50 mg of zinc gluconate daily plus conventional hospital management). OM severity was recorded at a two-month follow-up. RESULTS: Forty-nine patients (26 in the control group and 23 in the experimental group) were included. The mean age of the patients was 11.1 ± 2.7 years; 65.3% had a diagnosis of pre-B acute lymphoblastic leukemia. The incidences of OM in the control group and the experimental group were 46.2% and 26.1%, respectively, but the difference was not significant. Based on a negative binomial regression model, females had, on average, 1.5 more days with OM (p = 0.002), and patients assigned to the experimental group had, on average, 2 less days with OM than the control group (p = 0.001). The pain score was higher in the control group (p = 0.0009), as was the mean score on the WHO scale (p = 0.0012). CONCLUSIONS: Zinc facilitated a reduction in the severity and duration of OM; further studies focusing on children are needed to confirm the effects of this trace element.


Asunto(s)
Antineoplásicos , Leucemia , Mucositis , Estomatitis , Adolescente , Antineoplásicos/efectos adversos , Niño , Femenino , Humanos , Leucemia/tratamiento farmacológico , Estomatitis/inducido químicamente , Estomatitis/tratamiento farmacológico , Estomatitis/prevención & control , Zinc
15.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 5464-5467, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-33019216

RESUMEN

In vitro cytotoxicity screening is a crucial step of anticancer drug discovery. The application of deep learning methodology is gaining increasing attentions in processing drug screening data and studying anticancer mechanisms of chemical compounds. In this work, we explored the utilization of convolutional neural network in modeling the anticancer efficacy of small molecules. In particular, we presented a VGG19 model trained on 2D structural formulae to predict the growth-inhibitory effects of compounds against leukemia cell line CCRF-CEM, without any use of chemical descriptors. The model achieved a normalized RMSE of 15.76% on predicting growth inhibition and a Pearson Correlation Coefficient of 0.72 between predicted and experimental data, demonstrating a strong predictive power in this task. Furthermore, we implemented the Layer-wise Relevance Propagation technique to interpret the network and visualize the chemical groups predicted by the model that contribute to toxicity with human-readable representations.Clinical relevance-This work predicts the cytotoxicity of chemical compounds against human leukemic lymphoblast CCRF-CEM cell lines on a continuous scale, which only requires 2D images of the structural formulae of the compounds as inputs. Knowledge in the structure-toxicity relationship of small molecules will potentially increase the hit rate of primary drug screening assays.


Asunto(s)
Descubrimiento de Drogas , Leucemia , Evaluación Preclínica de Medicamentos , Humanos , Leucemia/tratamiento farmacológico , Aprendizaje Automático , Redes Neurales de la Computación
16.
Leuk Res ; 96: 106407, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32652329
17.
Adv Exp Med Biol ; 1207: 601-613, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32671778

RESUMEN

Leukemia is a malignant clonal disease that originates from hematopoietic stem cells. As in-depth research examines the molecular biology and immunology of the hematopoietic system, leukemia treatment has evolved from a single cytotoxic drug to treatments that inducing differentiation and apoptosis. Meanwhile, autophagy has become a growing concern as a new form of cell death. The immune response, hematopoietic stem cell differentiation, and drug resistance of tumor cells are all potentially affected by autophagy. Regulating autophagy may become one of the promising directions in the field of targeted therapy.


Asunto(s)
Autofagia , Leucemia , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Autofagia/efectos de los fármacos , Células Madre Hematopoyéticas/patología , Humanos , Leucemia/tratamiento farmacológico , Leucemia/patología
18.
Cancer Treat Rev ; 88: 102026, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32592909

RESUMEN

Progress in cancer therapy changed the outcome of many patients and moved therapy from chemotherapy agents to targeted drugs. Targeted drugs already changed the clinical practice in treatment of leukemias, such as imatinib (BCR/ABL inhibitor) in chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL), ibrutinib (Bruton's tyrosine kinase inhibitor) in chronic lymphocytic leukemia (CLL), venetoclax (BCL2 inhibitor) in CLL and acute myeloid leukemia (AML) or midostaurin (FLT3 inhibitor) in AML. In this review, we focused on DNA damage response (DDR) inhibition, specifically on inhibition of ATR-CHK1 pathway. Cancer cells harbor often defects in different DDR pathways, which render them vulnerable to DDR inhibition. Some DDR inhibitors showed interesting single-agent activity even in the absence of cytotoxic drug especially in cancers with underlying defects in DDR or DNA replication. Almost no mutations were found in ATR and CHEK1 genes in leukemia patients. Together with the fact that ATR-CHK1 pathway is essential for cell development and survival of leukemia cells, it represents a promising therapeutic target for treatment of leukemia. ATR-CHK1 inhibition showed excellent results in preclinical testing in acute and chronic leukemias. However, results in clinical trials are so far insufficient. Therefore, the ongoing and future clinical trials will decide on the success of ATR/CHK1 inhibitors in clinical practice of leukemia treatment.


Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/metabolismo , Leucemia/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Enfermedad Aguda , Animales , Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/antagonistas & inhibidores , Enfermedad Crónica , Daño del ADN , Humanos , Leucemia/genética , Leucemia/metabolismo , Leucemia/patología , Terapia Molecular Dirigida , Ensayos Clínicos Controlados Aleatorios como Asunto
20.
Int J Hematol ; 112(3): 409-417, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32557124

RESUMEN

We conducted a nationwide questionnaire-based survey in 2019 following 2001, 2007 and 2013 surveys to clarify the real-world management of infection during chemotherapy for acute leukemia in Japan. An online questionnaire was sent through SurveyMonkey® to member institutions of the Japan Adult Leukemia Study Group in June 2019. The questionnaire consisted of 52 multiple-choice questions covering prophylactic measures, screening and diagnostic tests, empirical antibiotic therapy, antifungal management, the usage of granulocyte-colony stimulating factor, and vaccinations against influenza and pneumococcus during intensive chemotherapy for acute leukemia. Questions associated with antimicrobial stewardship were also included. Usable responses were received from 163 of 218 (74.8%) institutions. Approximately, half (52.2%) of the institutes did not have infectious disease department. As antibiotic prophylaxis, fluoroquinolones (62%) were most commonly used in induction chemotherapy for acute myeloid leukemia. No prophylaxis accounted for 19% of the institutions, which has gradually increased compared to previous surveys. In empirical antibiotic therapy for febrile neutropenia, monotherapy with ß-lactam antibiotics was the most commonly used first-line therapy. De-escalation was not considered in 42.2% of the institutions. In conclusion, this study clarified the real-world management of infection during intensive chemotherapy for acute leukemia in 2019 and raised future issues in Japan.


Asunto(s)
Antibacterianos/administración & dosificación , Profilaxis Antibiótica/estadística & datos numéricos , Programas de Optimización del Uso de los Antimicrobianos , Quimioterapia de Inducción , Control de Infecciones/métodos , Leucemia/tratamiento farmacológico , Enfermedad Aguda , Antifúngicos/administración & dosificación , Utilización de Medicamentos , Femenino , Fluoroquinolonas/administración & dosificación , Humanos , Infecciones/diagnóstico , Japón , Masculino , Encuestas y Cuestionarios , Vacunación
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