RESUMEN
INTRODUCCIÓN: Cuadro clínico: La leucemia promielocítica aguda (LPA) representa el 5% a 20% de los casos de leucemia mieloide aguda (LMA) (1,2); sin embargo, entre pacientes de origen latino se ha reportado una frecuencia de 38%. En Perú, a pesar de que no se tienen reportes de la frecuencia de la leucemia promielocítica aguda (LPA), en un estudio realizado entre el año 1996 y 2008 en el Hospital Nacional Edgardo Rebagliati Martins se observó que el 52% y 38% de los pacientes con LPA se encontraban entre los grupos etarios de 16 - 40 años y 41 - 60 años, respectivamente (3). En pacientes con LPA sin tratamiento la mediana de sobrevida es menor a un mes, debido al sangrado descontrolado (4). Sin embargo, con los avances recientes en las terapias, la sobrevida ha mejorado y la mayoría de los pacientes alcanza la remisión completa y se mantiene. El tratamiento de la LPA comprende tres etapas: remisión o inducción, consolidación y mantenimiento. Del total de pacientes con LPA tratados con ácido trans-retinoico (ATRA) más quimioterapia con antraciclinas, el 10 % al 20% sufre una recaída. El objetivo de tratamiento de este grupo de pacientes es alcanzar la remisión molecular, con planes de proseguir con quimioterap
Asunto(s)
Humanos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Antraciclinas/uso terapéutico , Trióxido de Arsénico/uso terapéutico , Evaluación en Salud/economía , Eficacia , Análisis Costo-Beneficio/economíaRESUMEN
All-trans retinoic acid and arsenic trioxide are the leading choices for the treatment of acute promyelocytic leukemia. Notwithstanding the impressive differentiative properties of all-trans retinoic acid and the apoptotic properties of arsenic trioxide, some problems still occur in acute promyelocytic leukemia treatment. These problems are due to patients' relapses, mainly related to changes in the ligand-binding domain of RARα (retinoic acid receptor α) and the cardiotoxic effects caused by arsenic trioxide. We previously developed a self-nanoemulsifying drug delivery system enriched with tocotrienols to deliver all-trans retinoic acid (SNEDDS-TRF-ATRA). Herein, we have evaluated if tocotrienols can help revert ATRA resistance in an APL cell line (NB4-R2 compared to sensitive NB4 cells) and mitigate the cardiotoxic effects of arsenic trioxide in a murine model. SNEDDS-TRF-ATRA enhanced all-trans retinoic acid cytotoxicity in NB4-R2 (resistant) cells but not in NB4 (sensitive) cells. Moreover, SNEDDS-TRF-ATRA did not significantly change the differentiative properties of all-trans retinoic acid in both NB4 and NB4-R2 cells. Combined administration of SNEDDS-TRF-ATRA and arsenic trioxide could revert QTc interval prolongation caused by ATO but evoked other electrocardiogram alterations in mice, such as T wave flattening. Therefore, SNEDDS-TRF-ATRA may enhance the antileukemic properties of all-trans retinoic acid but may influence ECG changes caused by arsenic trioxide administration. SNEDDS-TRF-ATRA presents cytotoxicity in resistant APL cells (NB4-R2). Combined administration of ATO and SNEDDS-TRF-ATRA in mice prevented the prolongation of the QTc interval caused by ATO but evoked ECG abnormalities such as T wave flattening.
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Leucemia Promielocítica Aguda , Tocotrienoles , Animales , Ratones , Trióxido de Arsénico/farmacología , Trióxido de Arsénico/uso terapéutico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/metabolismo , Tocotrienoles/uso terapéutico , Tretinoina/farmacología , Tretinoina/uso terapéutico , Electrocardiografía , Óxidos/farmacología , Óxidos/uso terapéuticoRESUMEN
BACKGROUND AND PURPOSE: Arsenic trioxide (ATO) exerts anticancer effects on lung cancer. However, the clinical use of ATO is limited due to its systemic toxicity and resistance of lung cancer cells. The present study aimed to investigate the effects of ATO, alone and in combination with 125I seed implantation on tumor growth and proliferation in lung cancer xenograft mice, and investigate the possible molecular mechanisms. METHODS: The transmission electron microscope observed the tumor ultrastructure of lung cancer xenograft mice. The proliferation index of Ki-67 and the number and morphology of tumor microvessels were detected with immunohistochemical staining. The protein and mRNA expression were examined by western blot and real-time PCR assay. RESULTS: The in vivo results demonstrated that ATO combined with 125I seed significantly inhibited tumor growth and proliferation, as well as promoted apoptosis, and decreased the Ki-67 index and microvessel density in lung cancer xenograft mice. Moreover, ATO combined with 125I seed decreased the protein and mRNA expression levels of HIF-1α, VEGF, and BCL-2, and increased those of BAX and P53. CONCLUSIONS: ATO combined with 125I seed significantly inhibited tumor growth and proliferation in lung cancer, which may be accomplished by inhibiting tumor angiogenesis and inducing apoptosis.
Asunto(s)
Antineoplásicos , Neoplasias Pulmonares , Humanos , Animales , Ratones , Trióxido de Arsénico/uso terapéutico , Xenoinjertos , Antígeno Ki-67 , Ensayos Antitumor por Modelo de Xenoinjerto , Apoptosis , Neoplasias Pulmonares/patología , ARN Mensajero , Línea Celular Tumoral , Proliferación Celular , Antineoplásicos/uso terapéuticoRESUMEN
Background: Arsenic trioxide is a chemical compound that has been used as a treatment for various diseases. Despite being potentially toxic, this compound has been used as a therapy to treat Acute Myeloid Leukemia and is being investigated as a possible treatment for different types of cancer. Objectives: The present review aims to describe the use and studies reported in the literature of Arsenic Trioxide as a possible therapeutic agent for Acute Myeloid Leukemia, Acute Promyelocytic Leukemia, Chronic Myeloid Leukemia, Multiple Myeloma, Myelodysplastic Syndrome, Hepatocellular Carcinoma, Lung Cancer, Neuroblastoma, Breast Cancer, Aplastic Hepatitis C, and HIV-1. Methods: A systematic review was conducted using databases (Elsevier, Google Scholar, PubMed) to compile documents published before December 2023. Results:Multiple pharmacological applications of arsenic trioxide have been reported to treat acute and chronic myeloid leukemia. Arsenic trioxide has been shown to inhibit angiogenesis, which helps treat multiple myeloma. Several studies have shown and suggested the effectiveness of arsenic trioxide as a treatment of hepatocellular carcinoma, lung cancer, neuroblastoma, prostate cancer, breast cancer, aplastic anemia, hepatitis C, and HIV-1. Conclusion: Despite potentially toxic effects, Arsenic compounds are therapeutic agents for multiple diseases, from syphilis to cancer. In recent years, more efficient ways have been investigated to deliver and find the specific dose to treat the disease, causing the fewest possible adverse effects.
Antecedentes: El trióxido de arsénico es un compuesto químico que se ha utilizado como tratamiento de diversas enfermedades. A pesar de ser potencialmente tóxico, este compuesto se ha utilizado como terapia para tratar la leucemia mieloide aguda y se está investigando como posible tratamiento para diferentes tipos de cáncer. Objetivos: La presente revisión pretende describir el uso del trióxido de arsénico como posible agente terapéutico para la leucemia mieloide aguda, la leucemia promielocítica aguda, la leucemia mieloide crónica, el mieloma múltiple, el síndrome mielodisplásico, el carcinoma hepatocelular, el cáncer de pulmón, el neuroblastoma, el cáncer de mama, la hepatitis C aplásica y el VIH-1. Métodos: Se realizó una revisión sistemática utilizando bases de datos (Elsevier, Google Scholar, PubMed) para recopilar documentos publicados antes de diciembre de 2023. Resultados: Se ha informado de múltiples aplicaciones farmacológicas del trióxido de arsénico para tratar la leucemia mieloide aguda y la leucemia mieloide crónica. Se ha demostrado que el trióxido de arsénico inhibe la angiogénesis, lo que resulta útil para el tratamiento del mieloma múltiple. Varios estudios han demostrado y sugerido la eficacia del trióxido de arsénico como tratamiento del carcinoma hepatocelular, el cáncer de pulmón, el neuroblastoma, el cáncer de próstata, el cáncer de mama, la anemia aplásica, la hepatitis C y el VIH-1. Conclusión: A pesar de tener un efecto potencialmente tóxico, los compuestos de arsénico destacan como agentes terapéuticos para múltiples enfermedades, desde la sífilis hasta el cáncer. En los últimos años, se han investigado formas más eficientes de administrar y encontrar la dosis específica para poder tratar la enfermedad, causando los menores efectos adversos posibles.
Asunto(s)
Humanos , Trióxido de Arsénico , Carcinoma , Acciones Farmacológicas , NeoplasiasRESUMEN
Introducción. La leucemia promielocítica aguda (LPA) es un subtipo poco frecuente de leucemia mieloide aguda (LMA), que se caracteriza por un comportamiento clínico particularmente agresivo, y en ausencia de tratamiento, su curso generalmente es fatal. El objetivo de este trabajo fue determinar las características clínicas y citogenéticas de una cohorte de pacientes con LPA, con la finalidad de evaluar su relación con las complicaciones, el pronóstico y el desenlace de estos pacientes. Metodología. Se realizó un estudio observacional, descriptivo, retrospectivo de los pacientes mayores de 15 años con diagnóstico de LPA, atendidos en el Hospital Universitario San Vicente Fundación, entre los años 2012 a 2020. Resultados. Un total de 32 pacientes fueron incluidos. La edad media del diagnóstico fue 37 años. El 84,4% de los pacientes tenía la traslocación (15;17) en el cariotipo, y el 93,75% tenían FISH positivo. El 12,5% de los casos tenían cariotipo complejo. La mortalidad en los primeros 30 días fue del 15,6%, siendo el sangrado la causa de muerte más frecuente. Todos los pacientes que sobrevivieron alcanzaron la remisión completa (84,3%). En un promedio de seguimiento de 24 meses, el 14,8% de los casos recayeron. En el análisis bivariado se encontró relación entre sexo masculino y tener cariotipo complejo (p=0,015). No se encontró relación entre cariotipo complejo y mortalidad temprana (p=0,358), tampoco entre cariotipo complejo y recaída (p=0,052). Conclusiones. Se presentan las características clínicas y citogenéticas de una cohorte de pacientes con LPA en Colombia. El sangrado en el sistema nervioso central fue la principal causa de mortalidad temprana, todos los pacientes que sobrevivieron alcanzaron la remisión completa con la terapia de inducción. Las tasas de mortalidad, remisión completa y recaída fueron similares a las reportadas por otras series latinoamericanas, pero inferiores a estudios provenientes de países europeos. Contrario a lo reportado en otros estudios, no se encontró relación entre el cariotipo complejo y la mortalidad temprana o recaída.
Introduction. Acute promyelocytic leukemia (APL) is a rare subtype of acute myeloid leukemia (AML), characterized by a particularly aggressive clinical behavior, that in the absence of treatment is usually fatal. The objective of this work was to determine the clinical and cytogenetic characteristics of a cohort of patients with APL, in order to evaluate their relationship with the outcome and prognosis of these patients. Methodology. An observational, descriptive, retrospective study of patients older than 15 years with a diagnosis of APL treated at the Hospital Universitario San Vicente Fundación, between 2012 and 2020, was carried out. Results. A total of 32 patients were included. The mean age at diagnosis was 37 years, 84.4% of the patients had the t(15;17) in the karyotype, and 93.75% had positive FISH. 12.5% of cases had a complex karyotype. Mortality in the first 30 days was 15.6%, with bleeding being the most common cause of death. All patients who survived achieved complete remission (84.3%). In an average follow-up of 24 months, 14.8% of cases relapsed. In the bivariate analysis, a relationship was found between the male sex and having a complex karyotype (p<0.015). No relationship was found between complex karyotype and early mortality (p=0.358), nor between complex karyotype and relapse (p=0.052). Conclusions. We present the clinical and cytogenetic characteristics of a cohort of patients with APL in Colombia. Central nervous system bleeding was the main cause of early mortality, with all surviving patients achieving complete remission on induction therapy. Mortality, complete remission and relapse rates were similar to those reported by other Latin American series, but lower than studies from European countries. Contrary to what has been reported in other studies, no relationship was found between complex karyotype and early mortality or relapse
Asunto(s)
Leucemia Promielocítica Aguda , Tretinoina , Idarrubicina , Hibridación Fluorescente in Situ , Cariotipo , Trióxido de ArsénicoRESUMEN
Introducción: Con el protocolo LPM-TOA para el tratamiento de la leucemia promielocítica se obtienen excelentes resultados, se prolonga la sobrevida global y es posible la curación de los enfermos. En la de inducción a la remisión se utilizan dos drogas, una antraciclina y trióxido de arsénico, y en la consolidación los enfermos reciben de nuevo una dosis elevada de arsénico. Objetivo: Evaluar la toxicidad hepática tardía en pacientes con leucemia promielocítica tratados según el protocolo LPM-TOA. Métodos: Se realizó estudio longitudinal prospectivo que incluyó20 pacientes tratados con dicho protocolo, todos con más de dos años de haberlo suspendido. Se revisaron las historias clínicas para evaluar mediante los valores iniciales y evolutivos de las enzimas hepáticas, la función hepática inicial y evolutiva. Se determinó el índice de Ritis para predecir evolución a la cronicidad de existir daño hepático. Resultados: Hombres y mujeres se presentaron con la misma frecuencia y la media para la edad del sexo masculino fue 36,39 y para el femenino 39, con desviación estándar de ±14,02 y ±9,43, respectivamente. La variedad morfológica más frecuente fue la hipergranular, el promedio del índice de Ritis fue de solo 1,006 con desviación estándar de 0,745. Conclusiones: No hubo evidencias clínica ni enzimática de toxicidad hepática tardía en los pacientes estudiados(AU)
Introduction: With the LPM-TOA protocol for the treatment of acute promyelocytic leukemia, excellent results are obtained, overall survival is prolonged and the patients are cured, in the induction to remission two drugs are used, an anthracycline and arsenic trioxide, and in consolidation the patients again receive a high dose of arsenic. Objective: To assess late liver toxicity in patients with promyelocytic leukemia treated according to the PML-TOA protocol. Methods: A prospective longitudinal study was carried out that included 20 patients treated with this protocol, all with more than two years of having suspended treatment. The clinical histories were reviewed and by means of the initial and evolutionary values of liver enzymes, the initial and evolutionary liver function was evaluated and the Ritis index was determined to predict evolution to chronicity if there is liver damage. Results: Men and women presented with the same frequency and the mean age for males was 36.39 and for females it was 39, with a standard deviation of ± 14.02 and ± 9.43 respectively. The most frequent morphological variety was hypergranular, the average Ritis index was only 1.006 with a standard deviation of 0.745. Conclusions: There was no clinical or enzymatic evidence of late liver toxicity in the patients studied(AU)
Asunto(s)
Humanos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Trióxido de Arsénico/toxicidad , Análisis de Supervivencia , Estudios Prospectivos , Estudios LongitudinalesRESUMEN
HnRNP K protein is a heterogeneous nuclear ribonucleoprotein which has been proposed to be involved in the leukemogenesis of acute promyelocytic leukemia (APL), as well as in differentiation induced by all-trans retinoic acid (ATRA). We previously demonstrated a connection between SET and hnRNP K function in head and neck squamous cell carcinoma (HNSCC) cells related to splicing processing. The objective of this study was to characterize the participation of hnRNP K and SET proteins in ATRA-induced differentiation in APL. We observed higher (5- to 40-fold) levels of hnRNP K and SET mRNA in APL patients at the diagnosis phase compared with induction and maintenance phases. hnRNP K knockdown using short-hairpin RNA led to cell death in ATRA-sensitive NB4 and resistant NB4-R2 cells by apoptosis with SET cleavage. In addition, hnRNP K knockdown increased granulocytic differentiation in APL cells, mainly in NB4-R2 with ATRA. hnRNP K knockdown had an effect similar to that of treatment with U0126 (an meiosis-specific serine/threonine protein kinase/ERK inhibitor), mainly in NB4-R2 cells. SET knockdown in APL cells revealed that apoptosis induction in cells with hnRNP K knockdown occurred by SET cleavage rather than by reduction in SET protein. Transplantation of NB4-R2 cells into nude mice confirmed that arsenic trioxide (ATO) combined with U0126 has higher potential against tumor progression when compared to ATO. Therefore, hnRNP K/SET and ERK are potential therapeutic targets for both antineoplastic leukemia therapy and relapsed APL patients with ATRA resistance.
Asunto(s)
Leucemia Promielocítica Aguda , Animales , Trióxido de Arsénico/metabolismo , Trióxido de Arsénico/uso terapéutico , Ribonucleoproteína Heterogénea-Nuclear Grupo K/genética , Humanos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Ratones , Ratones Desnudos , Tretinoina/metabolismo , Tretinoina/farmacologíaRESUMEN
PURPOSE: APL patients have recurrent alterations in FLT3, WT1, NRAS and KRAS. Gene mutations have a strong potential for involvement in pathogenesis and may have potential effects on the clinical manifestations. Gene mutations may even be associated with early death (ED) in APL patients. However, there is little published information on mutations in APL patients and whether they are attributed to early death. METHODS: In this study, we retrospectively analyzed the clinical data and gene mutations of 134 de novo APL patients. We detected the gene mutations by next-generation sequencing (NGS) to investigate the genetic predictors of early death in APL patients. According to the number of gene mutations per patient, the 134 APL patients were divided into three groups. All patients received arsenic trioxide (ATO) alone as induction therapy. The clinical data and gene mutations were compared and analyzed. RESULTS: A total of 134 APL patients were involved in the study. The clinical data of sex, WBC, PT, and DD, UA, and LDH level were significantly different between the three groups (P = 0.000, P = 0.000, P = 0.009, P = 0.020, P = 0.030, P = 0.001 and P = 0.014, respectively). Meanwhile, among them, the Sanz risk stratification and early death rate were significantly different (P = 0.001). The early death rate was 10.4%, and the median time to early death was 6.6 days (range 2-15 days). For the next-generation sequencing, a mean of 1.28 ± 1.06 mutations per patient was detected (range: 0-5). The univariate and the multivariate regression analysis showed that age > 50[HR = 1.666, CI (1.027-2.702), P = 0.039], high WBC count [HR = 4.702, CI (1.026-21.543), P = 0.046] and low ALB levels [HR = 4.547, CI (1.088-18.995), P = 0.038] were independent risk factors for early death in APL patients. Furthermore, Kaplan-Meier survival analysis, univariate analysis, and the multivariate regression analysis showed that patients with multiple gene mutations [HR = 2.258, CI (1.115-4.571), P = 0.024], KRAS [HR = 5.136, CI (1.356-19.455), P = 0.016] and/or GATA2 [HR = 4.070, CI (1.287-12.877), P = 0.017] have a significantly higher early death rate. CONCLUSION: The results of this investigation show that both molecular markers and clinical variables should be used as potential predictors for early death in APL patients. Our results suggested that age > 50, high WBC count, low ALB levels, and the presence of multiple gene mutations, KRAS and/or GATA2 at the time of diagnosis were independent risk factors for early death in APL patients. For these patients, clinicians should be more cautious during the course of induction treatment.
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Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/mortalidad , Mutación , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Trióxido de Arsénico/uso terapéutico , Causas de Muerte , Niño , Femenino , Factor de Transcripción GATA2/genética , Genes ras , Marcadores Genéticos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Quimioterapia de Inducción/métodos , Leucemia Promielocítica Aguda/sangre , Leucemia Promielocítica Aguda/tratamiento farmacológico , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Tiempo de Protrombina , Análisis de Regresión , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , Factores de Tiempo , Adulto JovenRESUMEN
The functionalization of polysaccharides with synthetic nanopolymers has attracted great attention owing to the applications of this method in many industrial fields. This work aimed to investigate the effect of arsenic trioxide on the functionalization of dextran. Dextran-arsenite nanoparticle formation was induced by microwave with sulfuric acid as a catalyst. Various analytical techniques were used to verify the structure of the nanopolymers. Besides, various reaction conditions, such as dextran concentration, arsenic trioxide concentration and pH, were investigated to determine their impact on particle size. The results indicated that the product was an arsenite-based nanomaterial retaining the basic configuration of dextran and that the product size was positively correlated with pH but negatively correlated with arsenic trioxide concentration. Moreover, the inhibitory effects of the dextran-arsenite nanoparticles on the growth of the human colorectal cancer cell line HCT-116 and human hepatoma carcinoma cell lines Huh-7 and SMMC-7721 were studied. The results showed that the product could inhibit the proliferation of these three tumor cell lines in a dose-dependent manner. Therefore, the product could be a new type of functional nanomaterial for further study on the synthesis, biological activity and development of polysaccharide drugs.
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Antineoplásicos , Arsenitos , Nanopartículas , Antineoplásicos/farmacología , Trióxido de Arsénico , Dextranos , HumanosRESUMEN
Introducción: Con el protocolo LPM-TOA para tratamiento de la leucemia promielocítica, se han obtenido excelentes resultados, ya que se logra sobrevida global prolongada y posible curación de los enfermos. En la inducción se utilizan dos drogas cardiotóxicas: las antraciclinas y el trióxido de arsénico y en la consolidación los enfermos reciben una dosis elevada de arsénico. Objetivo: Evaluar la toxicidad cardíaca tardía en pacientes con leucemia promielocítica tratados según el protocolo LPM-TOA. Métodos: Se realizó un estudio observacional descriptivo, prospectivo y longitudinal que incluyó 20 pacientes tratados con protocolo LPM-TOA, seguidos en consulta entre enero y julio 2019. Los pacientes tenían más de dos años de haber recibido las drogas cardiotóxicas. Se revisaron las historias clínicas y se determinó la fracción de eyección ventricular izquierda y la deformidad longitudinal global, mediante ecocardiograma. Resultados: Se presentaron hombres y mujeres con igual frecuencia, edad promedio 41,5 ± 11,0 años. Durante la inducción, en menos de la mitad de los enfermos se suspendió el arsénico por elevación del segmento QT corregido; en la mayoría solo se suspendió por uno o dos días. La mayor parte de los pacientes tuvo la fracción de eyección ventricular izquierda con valores entre 61 y 70 por ciento y la deformidad longitudinal global fue - 24 - 22 por ciento Conclusiones: En los pacientes estudiados, el tiempo de haber recibido el trióxido de arsénico y la dosis recibida, no influyó en la función cardíaca(AU)
Introduction: The PML-ATO protocol for the treatment of promyelocytic leukemia has obtained excellent results, achieving high overall survival rates and the possible healing of patients. Two cardiotoxic drugs are used in the induction process: anthracyclines and arsenic trioxide, whereas during consolidation patients receive a high dose of arsenic. Objective: Evaluate the late cardiotoxicity in patients with promyelocytic leukemia treated by the PML-ATO protocol. Methods: An observational prospective longitudinal descriptive study was conducted of 20 patients treated with the PML-ATO protocol and followed-up in outpatient consultation from January to July 2019. More than two years had elapsed since the patients received the cardiotoxic drugs. A review was carried out of the patients' medical records and echocardiographic determination was made of left ventricular ejection fraction and overall longitudinal deformity. Results: Men and women presented the same frequency; mean age was 41.5 ± 11.0 years. During induction, arsenic was suspended in less than half the patients due to corrected QT elevation. In most it was only suspended for one or two days. Most patients had left ventricular ejection fraction values between 61 percent and 70 percent, whereas overall longitudinal deformity was - 24 percent - 22 percent. Conclusions: In the patients studied, cardiac function was not affected by the time elapsed since arsenic trioxide administration or the dose received(AU)
Asunto(s)
Humanos , Leucemia Promielocítica Aguda/mortalidad , Leucemia Promielocítica Aguda/terapia , Antraciclinas , Trióxido de Arsénico/uso terapéutico , Registros Médicos , Tasa de Supervivencia , Cardiotoxicidad/tratamiento farmacológicoRESUMEN
INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad del esquema de inducción trióxido de arsénico (TOA) más ácido transretinoico (ATRA, por sus siglas en inglés) y sin antraciclinas; comparado con el esquema ATRA más antraciclinas para el tratamiento de pacientes con diagnóstico de leucemia promielocítica aguda (LPA) de riesgo bajo o intermedio que hayan sido recién diagnosticados. La leucemia promielocítica aguda (LPA) es un subtipo infrecuente de leucemia mieloide aguda caracterizada por una anormalidad citogenética que involucra al gen del receptor alfa de ácido retinoico (RARα, por sus siglas en inglés). La LPA es una enfermedad infrecuente, con una incidencia menor a 0.6/100,000 habitantes. Actualmente, en EsSalud, el tratamiento de los pacientes con LPA consiste en el esquema ácido transretinoico (ATRA, por sus siglas en inglés) más antraciclinas (doxorubicina o daunorubicina). Los especialistas de EsSalud consideran que el esquema trióxido de arsénico (TOA) más ATRA, sin antraciclinas, lograría mayores tasas de sobrevida que los esquemas disponibles actualmente. Por este motivo, se ha enviado al IETSI la solicitud de evaluación del uso de TOA más ATRA, sin antraciclinas, en comparación con los esquemas ATRA más antraciclinas. METODOLOGÍA: Se llevó a cabo una búsqueda sistemática de la literatura con respecto a la eficacia y seguridad del esquema TOA más ATRA, sin antraciclinas en el tratamiento de pacientes adultos con LPA de riesgo bajo o intermedio recién diagnosticada. Se realizó tanto una búsqueda sistemática como una búsqueda manual en las páginas web de grupos dedicados a la investigación y educación en salud que elaboran guías de práctica clínica (GPC) y evaluaciones de tecnologías sanitarias (ETS). RESULTADOS: En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad. CONCLUSIONES: En la presente evaluación de tecnología sanitaria se presenta la evidencia recabada sobre la eficacia y seguridad del esquema TOA más ATRA en comparación con ATRA más antraciclinas para el tratamiento de pacientes adultos con LPA de riesgo bajo o intermedio, recién diagnosticada. Se recolectó la evidencia de tres GPC, tres ETS y dos ECA fase III. El equipo técnico del IETSI valoró los siguientes aspectos: i) La LPA es una enfermedad infrecuente con una alta tasa de respuesta al tratamiento, ii) La evidencia disponible muestra que el esquema TOA más ATRA ofrece las mismas tasas de sobrevida global, tasa de remisión, calidad de vida e incidencia de eventos adversos que el esquema ATRA más idarubicina, iii) Los esquemas de tratamiento ATRA más antraciclinas (doxorubicina o daunorubicina) han mostrado resultados similares a los observados con ATRA más idarubicina y iv) Ante las similitudes en la sobrevida global, tasa de remisión, incidencia de eventos adversos y calidad de vida, el precio de TOA resulta ser elevado y no es costo-oportuno para EsSalud. Por todo lo mencionado, el IETSI, no aprueba el uso de TOA para el tratamiento de pacientes adultos con LPA de riesgo bajo o intermedio, recién diagnosticada.
Asunto(s)
Humanos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Trióxido de Arsénico/uso terapéutico , Eficacia , Análisis Costo-BeneficioRESUMEN
We evaluated the potential effects of ATO in different pediatric SHH-MB cell lines (ONS-76: TP53-wild type; DAOY and UW402: TP53-mutated). MB cell lines molecular subgroup was confirmed and TP53 mutations were validated. Cell viability, clonogenicity and apoptosis were evaluated after ATO treatment at different concentrations (1-16 µM) alone or combined with irradiation doses (0.5, 1, 2 and 4 Gy). Rad51 and Ku86 proteins were evaluated by WB. ATO treatment reduced cell viability for all SHH-MB cell lines. Significant decrease of clonogenic capacity and higher apoptosis rates were also observed after ATO exposure, being cell death more pronounced (>70%) for the SHH-MB TP53-mutated. Combined treatment of ATO with irradiation also reduced colonies formation in UW402 tumor cells, which was independent of DNA damage repair proteins Rad51 and Ku86. In silico analyses suggested that a set of genes from cell cycle and p53 pathways are differentially expressed in SHH tumor subtypes, suggesting that cell lines may respond to therapies according to the gene expression profiles. Herein, we showed ATO cytotoxicity in pediatric SHH cell lines, with marked radiosensitizing effect for the MB-SHH TP53-mutated cells. These results highlight the potential of ATO, alone or in combination with radiotherapy, supporting further clinical investigations.
Asunto(s)
Apoptosis/efectos de los fármacos , Trióxido de Arsénico/farmacología , Meduloblastoma/tratamiento farmacológico , Fármacos Sensibilizantes a Radiaciones/farmacología , Línea Celular Tumoral , Niño , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Meduloblastoma/metabolismo , Meduloblastoma/patología , Proteínas de Neoplasias/metabolismoRESUMEN
Arsenic trioxide (ATO), a highly effective drug in treating acute promyelocytic leukemia with low toxicity, demonstrates a significant effect on lung cancer. The anti-cancer mechanisms of ATO include inhibition of cancer stem-like cells, induction of apoptosis, anti-angiogenesis, sensitization of chemotherapy and radiotherapy, anti-cancer effects of hypoxia, and immunoregulation properties. In addition, some studies have reported that different lung cancers respond differently to ATO. It was concluded on numerous studies that the rational combination of administration and encapsulation of ATO have promising potentials in increasing drug efficacy and decreasing adverse drug effects. We reviewed the efficacy of ATO in the treatment of lung cancer in recent years to provide some views for further study.
Asunto(s)
Antineoplásicos/uso terapéutico , Trióxido de Arsénico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Humanos , PronósticoRESUMEN
In this work, we investigated the stability of arsenic trioxide (ATO) used in leukemia treatment, encapsulated with nanoliposome, with the aid of ultrasound treatment. Stability studies of As species were followed by liquid chromatography-inductively coupled plasma mass spectrometry (LC-ICP-MS), allowing for the detection of the conversion of low amounts of As(III) to As(V) or the formation of other As species. The influence of storage temperature and time on ATO was evaluated. Low amounts of As(III) to As(V) conversions were observed when the As encapsulated with nanoliposome was incubated at 25 °C and 40 °C. However, As(III) was stable if the solution was maintained at 5 °C, even after 90 days. No formation of other As species was observed, indicating good stability of the encapsulated ATO. Next step of the work will focus on spray drying of ATO nanoliposomes-encapsuleted with the aim of long term stability of As.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/química , Trióxido de Arsénico/administración & dosificación , Trióxido de Arsénico/química , Antineoplásicos/farmacología , Trióxido de Arsénico/farmacología , Línea Celular Tumoral , Cromatografía Liquida , Estabilidad de Medicamentos , Humanos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Liposomas , Espectrometría de MasasRESUMEN
BACKGROUND: Arsenic trioxide (As2O3), a drug that has been used in China for approximately two thousand years, induces cell death in a variety of cancer cell types, including neuroblastoma (NB). The tyrosine kinase receptor (Trk) family comprises three members, namely TrkA, TrkB and TrkC. Various studies have confirmed that TrkA and TrkC expression is associated with a good prognosis in NB, while TrkB overexpression can lead to tumor cell growth and invasive metastasis. Previous studies have shown that As2O3 can inhibit the growth and proliferation of a human NB cell line and can also affect the N-Myc mRNA expression. It remains unclear whether As2O3 regulates Trks for the purposes of treating NB. METHODS: The aim of the present study was to investigate the effect of As2O3 on Trk expression in NB cell lines and its potential therapeutic efficacy. SK-N-SH cells were grown with increasing doses of As2O3 at different time points. We cultured SK-N-SH cells, which were treated with increasing doses of As2O3 at different time points. Trk expression in the NB samples was quantified by immunohistochemistry, and the cell cycle was analyzed by flow cytometry. TrkA, TrkB and TrkC mRNA expression was evaluated by real-time PCR analysis. RESULTS: Immunohistochemical and real-time PCR analyses indicated that TrkA and TrkC were over-expressed in NB, and specifically during stages 1, 2 and 4S of the disease progression. TrkB expression was increased in stage 3 and 4 NB. As2O3 significantly arrested SK-N-SH cells in the G2/M phase. In addition, TrkA, TrkB and TrkC expression levels were significantly upregulated by higher concentrations of As2O3 treatment, notably in the 48-h treatment period. Our findings suggested that to achieve the maximum effect and appropriate regulation of Trk expression in NB stages 1, 2 and 4S, As2O3 treatment should be at relatively higher concentrations for longer delivery times;however, for NB stages 3 and 4, an appropriate concentration and infusion time for As2O3 must be carefully determined. CONCLUSION: The present findings suggested that As2O3 induced Trk expression in SK-N-SH cells to varying degrees and may be a promising adjuvant to current treatments for NB due to its apoptotic effects.
Asunto(s)
Arsenicales/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glicoproteínas de Membrana/efectos de los fármacos , Neuroblastoma/metabolismo , Óxidos/farmacología , Receptor trkB/efectos de los fármacos , Trióxido de Arsénico , Línea Celular Tumoral/efectos de los fármacos , Línea Celular Tumoral/metabolismo , Humanos , Glicoproteínas de Membrana/metabolismo , Neuroblastoma/patología , Receptor trkB/metabolismoRESUMEN
BACKGROUND: Arsenic trioxide (As2O3), a drug that has been used in China for approximately two thousand years, induces cell death in a variety of cancer cell types, including neuroblastoma (NB). The tyrosine kinase receptor (Trk) family comprises three members, namely TrkA, TrkB and TrkC. Various studies have confirmed that TrkA and TrkC expression is associated with a good prognosis in NB, while TrkB overexpression can lead to tumor cell growth and invasive metastasis. Previous studies have shown that As2O3 can inhibit the growth and proliferation of a human NB cell line and can also affect the N-Myc mRNA expression. It remains unclear whether As2O3 regulates Trks for the purposes of treating NB. METHODS: The aim of the present study was to investigate the effect of As2O3 on Trk expression in NB cell lines and its potential therapeutic efficacy. SK-N-SH cells were grown with increasing doses of As2O3 at different time points. We cultured SK-N-SH cells, which were treated with increasing doses of As2O3 at different time points. Trk expression in the NB samples was quantified by immunohistochemistry, and the cell cycle was analyzed by flow cytometry. TrkA, TrkB and TrkC mRNA expression was evaluated by real-time PCR analysis. RESULTS: Immunohistochemical and real-time PCR analyses indicated that TrkA and TrkC were over-expressed in NB, and specifically during stages 1, 2 and 4S of the disease progression. TrkB expression was increased in stage 3 and 4 NB. As2O3significantly arrested SK-N-SH cells in the G2/M phase. In addition, TrkA, TrkB and TrkC expression levels were significantly upregulated by higher concentrations of As2O3 treatment, notably in the 48-h treatment period. Our findings suggested that to achieve the maximum effect and appropriate regulation of Trk expression in NB stages 1, 2 and 4S, As2O3 treatment should be at relatively higher concentrations for longer delivery times;however, for NB stages 3 and 4, an appropriate concentration and infusion time for As2O3 must be carefully determined. CONCLUSION: The present findings suggested that As2O3 induced Trk expression in SK-N-SH cells to varying degrees and may be a promising adjuvant to current treatments for NB due to its apoptotic effects.
Asunto(s)
Humanos , Óxidos/farmacología , Arsenicales/farmacología , Glicoproteínas de Membrana/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Receptor trkB/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Neuroblastoma/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptor trkB/metabolismo , Línea Celular Tumoral/efectos de los fármacos , Línea Celular Tumoral/metabolismo , Trióxido de Arsénico , Neuroblastoma/patologíaRESUMEN
INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de trióxido de arsénico en pacientes adultos con diagnóstico de leucemia promielocítica aguda en recaída. El presente dictamen preliminar tuvo como objetivo identificar la evidencia científica disponible sobre la eficacia y seguridad de trióxido de arsénico (TOA), en comparación al ácido transretinoico total (ATRA) más quimioterapia, en pacientes adultos con diagnóstico de leucemia promielocítica aguda (LPA) en recaída. TECNOLOGÍA SANITARIA DE INTERÉS: El trióxido de arsénico (TOA) es un compuesto inorgánico cuya fórmula molecular es As 2 O 3 . TOA causa cambios morfológicos y fragmentación del ADN (apoptosis) en las células de LPA humanas NB4 in vitro. También causa daño o degradación de la proteína de fusión PML-RARα (European Medicines Agency 2018). METODOLOGÍA: Se realizó una búsqueda sistemática de literatura con el objetivo de identificar evidencia sobre la eficacia y seguridad de trióxido de arsénico en pacientes adultos con diagnóstico de leucemia promielocítica aguda en recaída. Se utilizaron las bases de datos The Cochrane Library, Medline y el metabuscador TRIP Database, priorizándose la evidencia proveniente de revisiones sistemáticas o metaanálisis de ensayos clínicos controlados aleatorizados. RESULTADOS: Como resultado de nuestra búsqueda sistemática de literatura, se identificaron dos guías de práctica clínica (GPC) elaboradas por la organización americana NCCN (2018) y la sociedad japonesa JSH (2017), y dos evaluaciones de tecnologías sanitarias (ETS) elaboradas por la agencia británica NICE (2018) y la agencia canadiense CADTH (2014). No se identificaron ensayos clínicos aleatorizados (ECA) que respondan a la pregunta PICO establecida en el presente dictamen. ï Ambas GPC recomendaron el uso de TOA en pacientes con LPA en recaída. Dicha recomendación se sustentó con la evidencia de estudios de baja calidad metodológica, es decir, estudios observacionales de un solo brazo, sin grupo de comparación y con tamaño de muestra pequeño, que informaron tasas de remisión completa y sobrevida global a 2 años de 80 a 90 % y 50 a 70 %, respectivamente. No se reportaron resultados para la calidad de vida. Tampoco se evaluaron otras alternativas de tratamiento en este escenario clínico, aun cuando se sabe que ATRA más quimioterapia es una opción de tratamiento que ha sido utilizada ampliamente en esta condición, y que sigue siendo usada en países como el nuestro, en donde TOA no se encuentra disponible. CONCLUSIONES: al momento no existe evidencia científica que permita concluir que TOA ofrezca un beneficio neto adicional al tratamiento alternativo disponible en EsSalud, esto es, ATRA más quimioterapia, en pacientes adultos con diagnóstico de leucemia promielocítica aguda en recaída. Los estudios que sustentan el uso de TOA son estudios prospectivos de un solo brazo y con un pequeño tamaño de muestra, los cuales, al no presentar el grupo de comparación de interés, no permiten concluir que un tratamiento sea superior, equivalente o inferior a otro. Cabe resaltar, que los efectos de TOA en la sobrevida global, remisión clínica y seguridad reportados en estos estudios de baja calidad metodológica son similares a los reportados en los estudios disponibles para ATRA más quimioterapia en nuestra población de interés. Además, ATRA más quimioterapia es un régimen que sigue siendo recomendado en guías de práctica clínica de países con contextos económicos similares al nuestro. Es importante mencionar que TOA no cuenta con registro sanitario en nuestro país, por lo que no se comercializa en el mercado nacional. Además, se debe tener en consideración que cualquier decisión de aprobación de uso de un medicamento no disponible en el mercado nacional está condicionada a previa autorización por la Autoridad Nacional de Productos Farmacéuticos. En consecuencia, y sobre la base de los argumentos expuestos, el Instituto de Evaluación de Tecnologías en Salud e Investigación no aprueba el uso de TOA para el tratamiento de pacientes adultos con LPA en recaída.
Asunto(s)
Humanos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Trióxido de Arsénico/uso terapéutico , Evaluación de la Tecnología Biomédica , Análisis Costo-EficienciaRESUMEN
The acute promyelocytic leukemia (APL) is a rare disease, affecting 0.1/100,000 individuals globally. Despite significant advances in APL therapy, some patients still experience relapsed disease. Currently, arsenic trioxide (As2O3) was found to be effective in relapsed APL treatment and considered as standard treatment for these cases. However, it has been shown that exposure to As2O3 may exert adverse effects on the male reproductive system since this substance might also induce apoptosis of other important cell types including stem cells. Studies demonstrated that treatment with this metallic substance decreased plasma levels of testosterone and interfered with sperm parameters such as concentration, motility, and viability. In addition, As2O3 was found to produce significant damage to spermatocytes, which may be associated with testicular toxicity and consequent inhibition of spermatogenesis. The aim of this study was to determine sub-chronic treatment effects of As2O3 on sperm and testicular morphology, androgen receptor (AR) immunoreactivity in testes and epididymis, in addition to evaluation of fertility parameters in adult male mice. Thirty adult Swiss mice were divided into three experimental groups: control; received distilled water (vehicle) while treated received 0.3 or 3 mg/kg/day As2O3 subcutaneously, for 5 days per week, followed by 2 days of interruption, for 5 weeks. Results showed that As2O3 (1) decreased spermatozoa number, (2) produced seminiferous epithelium degeneration and exfoliation of germ cells tubule lumen (3) altered nucleus/cytoplasm proportion of Leydig cells and (4) reduced AR immunoreactivity in both Leydig and epithelial epididymal cells. Further, fetal viability tests demonstrated an increase in post-implantation loss in females that were mated with As2O3-treated males. Data indicate that As2O3 exposure altered the spermatogenic process and subsequently fetal viability.
Asunto(s)
Viabilidad Fetal/efectos de los fármacos , Óxidos/toxicidad , Testículo/efectos de los fármacos , Animales , Trióxido de Arsénico , Arsenicales/administración & dosificación , Modelos Animales de Enfermedad , Epidídimo/efectos de los fármacos , Epidídimo/metabolismo , Fertilidad/efectos de los fármacos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Células Intersticiales del Testículo/efectos de los fármacos , Células Intersticiales del Testículo/metabolismo , Masculino , Ratones , Óxidos/administración & dosificación , Receptores Androgénicos/metabolismo , Reproducción/efectos de los fármacos , Epitelio Seminífero/efectos de los fármacos , Epitelio Seminífero/metabolismo , Espermatogénesis/efectos de los fármacos , Espermatozoides/efectos de los fármacos , Espermatozoides/metabolismo , Testículo/metabolismo , Pruebas de Toxicidad Subcrónica , Aumento de Peso/efectos de los fármacosRESUMEN
Ki-1/57 is a nuclear and cytoplasmic regulatory protein first identified in malignant cells from Hodgkin's lymphoma. It is involved in gene expression regulation on both transcriptional and mRNA metabolism levels. Ki-1/57 belongs to the family of intrinsically unstructured proteins and undergoes phosphorylation by PKC and methylation by PRMT1. Previous characterization of its protein interaction profile by yeast two-hybrid screening showed that Ki-1/57 interacts with proteins of the SUMOylation machinery, the SUMO E2 conjugating enzyme UBC9 and the SUMO E3 ligase PIAS3, which suggested that Ki-1/57 could be involved with this process. Here we identified seven potential SUMO target sites (lysine residues) on Ki-1/57 sequence and observed that Ki-1/57 is modified by SUMO proteins in vitro and in vivo. We showed that SUMOylation of Ki-1/57 occurred on lysines 213, 276, and 336. In transfected cells expressing FLAG-Ki-1/57 wild-type, its paralog FLAG-CGI-55 wild-type, or their non-SUMOylated triple mutants, the number of PML-nuclear bodies (PML-NBs) is reduced compared with the control cells not expressing the constructs. More interestingly, after treating cells with arsenic trioxide (As2O3), the number of PML-NBs is no longer reduced when the non-SUMOylated triple mutant Ki-1/57 is expressed, suggesting that the SUMOylation of Ki-1/57 has a role in the control of As2O3-induced PML-NB formation. A proteome-wide analysis of Ki-1/57 partners in the presence of either SUMO-1 or SUMO-2 suggests that the involvement of Ki-1/57 with the regulation of gene expression is independent of the presence of either SUMO-1 or SUMO-2; however, the presence of SUMO-1 strongly influences the interaction of Ki-1/57 with proteins associated with cellular metabolism, maintenance, and cell cycle.
Asunto(s)
Factores Reguladores Miogénicos/metabolismo , Mapeo de Interacción de Proteínas , Procesamiento Proteico-Postraduccional , Proteínas de Unión al ARN/metabolismo , Proteína SUMO-1/metabolismo , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/metabolismo , Trióxido de Arsénico , Arsenicales/farmacología , Ciclo Celular/genética , Núcleo Celular/efectos de los fármacos , Núcleo Celular/genética , Núcleo Celular/metabolismo , Clonación Molecular , Escherichia coli/genética , Escherichia coli/metabolismo , Células HEK293 , Células HeLa , Humanos , Lisina , Factores Reguladores Miogénicos/genética , Oligopéptidos/genética , Oligopéptidos/metabolismo , Óxidos/farmacología , Plásmidos/química , Plásmidos/metabolismo , Unión Proteica , Biosíntesis de Proteínas , Proteínas de Unión al ARN/genética , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Proteína SUMO-1/genética , Proteínas Modificadoras Pequeñas Relacionadas con Ubiquitina/genética , Sumoilación , Transcripción GenéticaRESUMEN
Recent innovations in the genomic understanding of medulloblastomas have provided new ways to explore this highly invasive malignant brain cancer arising from the cerebellum. Among the four different medulloblastoma subgroups described to date, the sonic hedgehog (SHH) genetic pathway is the pathway activated in the tumorigenesis of medulloblastoma. SHH-related medulloblastomas are usually of nodular/desmoplastic histology and frequently occur in children under the age of three, an age group highly susceptible to the acute and long-term effects of treatment. Several new drugs aimed at SHH modulation are currently under development. This review focuses on the role of arsenic trioxide, a drug well established in clinical practice and probably an under-explored agent in medulloblastoma management, in the SHH pathway.